Component Processes

v
Absorption – entry of a drug from its site of
administration to the systemic circulation
vDistribution – process by which a drug enters
the interstitium or tissues from the blood
v
Metabolism / Biotransformation – processes by
which a drug is changed: to its active form or to
its removable form
v
Excretion – removal of the drug from the body
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Drug
Absorption into Plasma
Distribution to
Tissues
Bound Drug
Free Drug
Tissue
Storage
Sites of
Action
Drug Metabolism: Liver, Lung,
etc
Drug Excretion: Renal, Biliary,
etc.
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Permeation
v
Permeation – travel of a drug across
cellular membranes, influencing its
biodisposition; is dependent on:
Ø
Solubility
Ø
Ionization
Ø
Concentration gradient
Ø
Surface area
Ø
Tissue vascularity
Ø
Solubility
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§
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§
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ØIonization
§
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) sc!ub!c
§
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druºs
Ø
Concentration gradient – diffusion is down a
concentration gradient
ØSurface area – the larger the surface area,
the better the permeation
ØTissue vascularity – the better the
vascularity, the better the permeation
Absorption
v
Passive diffusion – most common
Ø
Aqueous diffusion: Fick’s Law:


Flux (J) = (C1 – C2) x S.A. x P.
coefficient

Thickness
§
J = molecules per unit time
§
C1= higher concentration
§
C2 = lower concentration
§
S.A. = surface area available for diffusion
§ P. Coefficient = permeability coefficient /
partition coefficient
§
Thickness = length of the diffusion path

Absorption
Ø
Lipid diffusion: the Henderson–
Hasselbalch equation

log (protonated / unprotonated)
= pKa – pH

*for acids: pKa = pH + log x
concentration [HA] unionized


concentration [A]

*if [A] = [HA], then pKa = pH + log
(1); log (1) = 0, so

pKa = pH


*for bases: pKa = pH + log x
concentration [BH+] ionized

concentration [B]

*if [B] = [BH+], then pKa = pH + log
(1); log (1) = 0, so

pKa = pH
weak Acids & weak Bases
vA weak acid is a neutral molecule that dissociates
into an anion & a proton (H+) so that its
protonated form is neutral, more lipid-soluble
vA weak base is a neutral molecule that can form a
cation by combining with a proton so its
protonated form is charged, water-soluble
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Diffusion
v
Aqueous diffusion
Ø
within large
aqueous
compartments
Øacross tight
junctions
Øacross
endothelium
thru pores
(MW20,000 -
30,000)
Ø
molecules tend
to move from
an area of
higher to an
area of lower
concentration
Ø
plasma protein-
bound drugs
cannot
permeate thru
aqueous pores
Ø
charged drugs
will be
influenced by
electric fields
v
Lipid diffusion
Ø
higher partition
coefficient =
easier for a drug
to enter lipid
phase from
aqueous
Ø
charged drugs –
difficulty in
diffusing thru
lipid
Ø
uncharged – lipid-
soluble
Ø
lower pH relative
to pKa, greater
fraction of
protonated drug
(protonated
form of an acid
is neutral;
protonated form
of a base is
charged)
Ø
A weak acid at
acid pH & a
weak base at
alkaline pH will
be more lipid-
soluble
Special Carriers
v
Facilitated diffusion – passive (no E
expended) carrier-mediated
transport.
Ø
saturable;
Ø
subject to competitive & non-
competitive inhibition
Ø
used by peptides, amino acids, glucose
v
Active (uses E) carrier-mediated
transport
Ø
saturable
Ø
subject to competitive & non-
competitive inhibition
Ø
against a concentration gradient
Ø
e.g. Na – K pump
Endocytosis & Exocytosis

ENDOCYTOSIS
v
entry into cells by very large substances
(uses E)
v
e.g. Iron & vit B12 complexed with their
binding proteins into intestinal mucosal
cells

EXOCYTOSIS
v
expulsion of substances from the cells
into the ECF (uses E)
v
e.g. Neurotransmitters at the synaptic
junction
Ion Trapping
v
Ion trapping or reabsorption – delays
excretion
ØKidneys:
§
ncur!v u!!druºs urc ¡!!!crcd u! !hc
º!cm cru!us
§
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bc rcubscrbcd bv nuss!vc d!¡¡us!cn
§
: !c !ncrcusc cxcrc!!cn chunºc ur!nurv
nH !c ¡uvcr !hc churºcd ¡crm c¡ !hc
( ) druº nc! rcud!!v ubscrbcd
– «cuk uc!ds urc cxcrc!cd ¡us!cr !n
( ) u!ku!!nc nH un!cn ¡crm ¡uvcrcd
– «cuk buscs urc cxcrc!cd ¡us!cr !n
( ) uc!d!c nH cu!!cn ¡crm ¡uvcrcd
ØOther sites: body fluids where pH differs
from blood pH, favoring trapping or
reabsorption
§
stomach contents ▪ aqueous humor
§
small intestines ▪ vaginal secretions
§
breast milk ▪ prostatic secretions
Distribution
v
First pass effect – decreased bioavailability
of drugs administered orally because of
initial absorption into the portal
circulation & distribution in the liver
where they may undergo metabolism or
excretion into bile
v
Extraction Ratio – magnitude of the first
pass effect.

ER = cl Liver / q (hepatic blood flow)
v
Systemic drug bioavailability – determined
from extent of absorption & ER.

F = f x (1 – ER)
v
Distribution
v
Volume of Distribution – ratio
between the amount of drug in the
body (dose given) & the
concentration of the drug in blood
plasma. Vd = drug in body / drug in
blood

Factors influencing Vd:
Ø
drug pKa (permeation)
Ø
extent of drug-plasma protein binding
Ø
lipid solubility (partition coefficient)
Ø
patient age, gender, disease states,
body composition
v
Drug – Plasma Protein
Binding
v
Most drugs are bound to some extent to
plasma proteins Albumin, Lipoproteins,
alpha 1 acid glycoprotein
v
Extent of protein binding parallels drug
lipid solubility
v
Binding of drug to Albumin is often non-
selective,
v
Acidophilic drugs bind to Albumin,
basophilic drugs bind to Globulins
v
drugs with similar chemical/physical
properties may compete for the same
binding sites
v
Volume of distribution is inversely
proportional to protein binding
v
Distribution
v
Non-ionized (hydrophobic) drugs cross
biomembranes easily
v
Binding to plasma proteins accelerates
absorption into plasma but slows
diffusion into tissues
v
Unbound / free drug crosses
biomembranes
v
Competition between drugs may lead to
displacement of a previously bound drug
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v
v
v
Distribution
v
Special barriers to distribution:
Øplacenta
Øblood-brain barrier
v
Many disease states alter distribution:
ØEdematous states – cirrhosis, heart failure,
nephrotic syndrome – prolong distribution
& delay Clearance
Ø
Obesity allows for greater accumulation of
lipophilic agents within fat cells,
increasing distribution & prolonging half-
life
Ø
Pregnancy increases intravascular volume,
thus increasing distribution
ØhypoAlbuminemia allows drugs that
normally bind to it to have increased
bioavailability
Ø
Renal failure may decrease drug bound
fraction (metabolite competes for protein
binding sites) & thus ↑ free drug levels

Blood Brain Barrier (BBB):

Only lipid-soluble compounds get through
the BBB.

Four components to the blood-brain barrier:

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Exceptions to the BBB. Certain parts of the
brain are not protected by the BBB:

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Meningitis: It opens up the blood brain
barrier due to edema. Thus Penicillin-G can
be used to treat meningitis (caused by
Neisseria meningitides), despite the fact
that it doesn't normally cross the BBB.
Penicillin-G is also actively pumped back
out of the brain once it has crossed the BBB.

Sites of Concentration: can affect the Vd

Fat, Bone, any Tissue, Transcellular sites: drug
concentrates in Fat / Bone / non-Plasma
locations  low r
on ntr t on o ru n
l sm  r V
Metabolism

Biotransformation of drugs (usually in the Liver;
also in the Lungs, Skin, Kidney, GIT)) to more
polar, hydrophilic, biologically inactive molecules;
required for elimination from the body.
vPhase I reactions – alteration of the parent drug
by exposing a functional group; active drug
transformed by phase I reactions usually lose
pharmacologic activity, while inactive prodrugs
are converted to biologically active metabolites
v
Phase II reactions – parent drug undergoes
conjugation reactions (to make them more
soluble) that form covalent linkages with a
functional group: glucuronic acid, acetyl coA,
sulfate, glutathione, amino acids, acetate, S-
adenosyl-methionine
Metabolism

Phase I
v
reaction products may be directly excreted in
urine or react with endogenous compounds to
form water-soluble conjugates
v
mixed function oxidase system (cytochrome
P450 enzyme complex: Cyt P450 enzyme,
Cyt P450 reductase) requires NADPH (not
ATP) as E source, & molecular O2; [drug
metabolizing enzymes are located in hepatic
microsomes: lipophilic, endoplasmic reticulum
membranes (SER)]
v
Phase I enzymes perform multiple types of
reactions:
§ O\TD\TT\l Rl\CTTONS
§ RlD|CTT\l Rl\CTTONS
§ HYDROlYTTC Rl\CTTONS
v

CYTOCHROME-P450 COMPLEX:

There are multiple isotypes.

CYT-P450-2, CYT-P450-3A are responsible for the
metabolism of most drugs.

CYT-P450-3A4 metabolizes many drugs in the GIT,
decreasing the bioavailability of many orally
absorbed drugs.

INDUCERS of CYT-P450 COMPLEX: Drugs that
increase the production or ↓ degradation of Cyt-
P450 enzymes.

Phenobarbital, Phenytoin, Carbamazepine induce
CYT-P450-3A4

Phenobarbital, Phenytoin also induce CYT-P450-
2B1

Polycyclic Aromatics (PAH): Induce CYT-P450-1A1

Glucocorticoids induce CYT-P450-3A4

Chronic Alcoholism, Isoniazid induce CYT-P450-
2E1. important! this drug activates some
carcinogens e.g. Nitrosamines.

*Chronic alcoholics have up-regulated many of
their CYT-P450 enzymes.



INHIBITORS of CYT-P450 COMPLEX

Inhibit production: Ethanol suppresses many
of the CYT-P450 enzymes, explaining some
of the drug-interactions of acute alcohol
use.

Non–competitive inhibition: Chloramphenicol
is metabolized by Cyt P450 to an alkylating
metabolite that inactivates Cyt P450

Competitive inhibition: Erythromycin inhibits
CYT-P450-3A4. Terfenadine (Seldane) is
metabolized by CYT-P450-3A4, so the toxic
unmetabolized form builds up in the
presence of Erythromycin. The
unmetabolized form is toxic and causes
lethal arrhythmias. This is why Seldane was
taken off the market;

Cimetidine, Ketoconazole – bind to the
heme in Cyt P450, decreasing metabolism of
Testosterone & other drugs

Steroids: Ethinyl estradiol,
Norethindrone; Spironolactone;
Propylthiouracil (PTU): inactivate Cyt P450
by binding the heme
Metabolism

Phase II
vDrug Conjugation reactions: “detoxification”
rxns: non-microsomal, primarily in the liver;
also in plasma & GIT – usually to
glucuronides, making the drug more soluble.
vconjugates are highly polar, generally
biologically inactive (exception: morphine
glucuronide – more potent analgesic than the
parent compound) & tend to be rapidly
excreted in urine or bile
v
“Enterohepatic recirculation”: high molecular
weight conjugates are more likely to be
excreted in bile  nt st n s w r
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t s st m r ul t on
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l m n t on
prolon t on o ru
ts
v
conjugation, hydrolysis, oxidation,
reduction
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Toxicity
v
drugs are metabolized to toxic
products
v
hepatotoxicity exhibited by
Ø
acyl glucuronidation of NSAIDS
Ø
N-acetylation of Isoniazid
Ø
Acetaminophen in high doses –
glucuronidation & sulfation are
usual conjugation reactions in
therapeutic doses, but in high
doses, these get saturated so Cyt
P450 metabolizes the drug, forming
hepatotoxic reactive electrophilic
metabolites  ulm n nt
p totox t · ·
t ( nt ot N
t l st n
Reduction in Bioavailability
v
First pass effect
v
Intestinal flora metabolize the drug
v
Drug is unstable in gastric acid e.g.
Penicillin
v
Drug is metabolized by digestive
enzymes e.g. Insulin
v
Drug is metabolized by intestinal wall
enzymes e.g. sympathomimetic
drugs / catecholamines
Excretion
v
Clearance – CL – removal of drug from the
blood, or the amount of blood/plasma
that is completely freed of drug per unit
time over the plasma concentration of
the drug

CL = rate of elimination of drug

plasma drug concentration
Ø
especially important for ensuring
appropriate long-term dosing, or
maintaining correct steady state drug
concentrations
Ø
Renal clearance - unchanged drug, water-
soluble metabolites – glomerular filtration,
active tubular secretion, passive tubular
reabsorption of lipid-soluble agents
Ø
Hepatic clearance – extraction of drugs after
GIT absorption






Excretion
v
Half life (t ½) – time required to decrease
the amount of drug in the body by 50%
during elimination or during a constant
infusion; useful in
Ø
estimating time to steady-state:
approximately 4 half-lives to reach 94%
Ø
Estimation of time required for drug
removal from the body
ØEstimation of appropriate dosing interval:
drug accumulation occurs when dosing
interval is less than 4 half-lives

Affected by
ØChronic renal failure – decreases clearance,
prolongs half-life
Ø
increasing Age – Vd changes, prolongs half-
life
Ø
Decreased plasma protein binding shortens
half-life
Drug Elimination
v
Zero order kinetics – rate of elimination
of the drug is constant regardless of
concentration i.e. constant amount of
drug eliminated per unit time so that
concentration decreases linearly with
time

examples: ethanol, phenytoin, aspirin
v
First order kinetics – rate of elimination
of the drug proportional to concentration
i.e. constant fraction of the drug
eliminated per unit time so that
concentration decreases exponentially
over time
Excretion
v
KIDNEY
Ø
GLOMERULAR FILTRATION: Clearance of
the apparent volume of distribution by
passive filtration.
§ Drug with MW < 5000 ------> it is completely filtered.
§ Inulin is completely filtered, and its clearance can be
measured to estimate Glomerular Filtration Rate
(GFR).
ØTUBULAR SECRETION: Active secretion.
§ Specific Compounds that are secreted:
– para-Amino Hippurate (PAH) is completely
secreted, so its clearance can be measured to
estimate Renal Blood Flow (RBF).
– Penicillin-G is excreted by active secretion.
Probenecid can be given to block this
secretion.
§
Anionic System: The anionic secretory
system generally secretes weak ACIDS:
– Penicillins, Cephalosporins
– Salicylates
– Thiazide Diuretics
– Glucuronide conjugates
§ Cationic System: The cationic secretory
system generally secretes BASES, or
things that are positively charged.
§
Ion-Trapping: Drugs can be "trapped" in
the urine, and their rate of elimination can
be increased, by adjusting the pH of the
urine to accommodate the drug. This is
useful to make the body get rid of poisons
more quickly.
– To increase excretion of acidic drugs, make
the urine more basic (give HCO3-)
– To increase excretion of basic drugs, make
the urine more acidic.
ØBILIARY EXCRETION: Some drugs are
actively secreted in the biliary tract and
excreted in the feces. Some of the drug
may be reabsorbed via the enterohepatic
circulation.
§ Transporters: The liver actively transporters
generally large compounds (MW > 300), or
positive, negative, or neutral charge.
– Anionic Transporter: Transports some acids,
such as Bile Acids, Bilirubin Glucuronides,
Glucuronide conjugates, Sulfobromophthalein,
Penicillins
– Neutral Transporter: Transports lipophilic
agents, such as:
» Steroids
» Ouabain
Ø
Cationic Transporter: Transports
positively charged agents, such as n-
Methylnicotinamide, tubocurarine
ØCharcoal can be given to increase the fecal
excretion of these drugs and prevent
enterohepatic reabsorption.
ØCholestyramine can be given to increase
the rate of biliary excretion of some drugs.
v
ORDERS of EXCRETION:
Ø
ZERO-ORDER EXCRETION: The rate
of excretion of a drug is
independent of its concentration.
§
General properties:
– dC/dt = -K
– A plot of the drug-concentration -vs- time is
linear.
– The half-life of the drug becomes continually
shorter as the drug is excreted.
§
Examples:
– Ethanol is zero-order in moderate
quantities, because the metabolism
system is saturated. The rate of
metabolism remains the same no matter
what the concentration.
– Phenytoin and Salicylates follow zero-
order kinetic at high concentration.
v
Ø FIRST-ORDER EXCRETION: The rate of excretion of
a drug is directly proportional to its concentration.
§ General properties:
– dC/dt = -K[C]
– A plot of the log[conc] -vs- time is linear. slope of the
line = -Kel / 2.303
– The half-life of the drug remains constant throughout its
excretion




• HALF-LIFE: The half-life is inversely proportional to the Kel,
constant of elimination. The higher the elimination
constant, the shorter the half-life.
v
v
v
COMPARTMENTS:
Ø
One-Compartment Kinetics:
Kinetics are calculated based on the
assumption that the drug is
distributed to one uniform
compartment.
§ One compartment kinetics implies that the
drug has a rapid equilibrium between
tissues and the blood, and that the release
of the drug from any tissues is not rate-
limiting in its excretion.
§ One-compartment kinetics also assumes
that the drug is distributed instantaneously
throughout the body. This is only true for
IV infusion.
v
Ø
Multi-Compartment Kinetics: Most
drugs follow multi-compartment
kinetics to an extent.
§ Biphasic Elimination Curve: Many drugs
follow a biphasic elimination curve -- first a
steep slope then a shallow slope.
– STEEP (initial) part of curve ------> initial
distribution of the drug in the body.
– SHALLOW part of curve ------> ultimate renal
excretion of drug, which is dependent on
the release of the drug from tissue
compartments into the blood.

v
CLEARANCE: The apparent volume of
blood from which a drug is cleared
per unit of time.
Ø
CLEARANCE OF DRUG =
(Vd)x(Kel)
§
The higher the volume of distribution of the
drug, the more rapid is its clearance.
§
The higher the elimination constant, the
more rapid is its clearance.

§ This is based on the Dilution Principle:
– (Conc)(Volume) = (Conc)(Volume)
– Total Amount = Total Amount
Ø
MEANING: In first-order kinetics, drug
is cleared at a constant rate. A
constant fraction of the Vd is
cleared per unit time. The higher
the Kel, the higher is that fraction of
volume.
§
Drug Clearance of 120 ml/min ------> drug is
cleared at the same rate as GFR and is
not reabsorbed. Example = inulin
§
Drug clearance of 660 ml/min ------> drug is
cleared at the same rate as RPF and is
actively secreted, and not reabsorbed.
Example = PAH


BIOAVAILABILITY: The proportion of
orally-administered drug that
reaches the target tissue and has
activity.
v
§ AUCORAL = Area under the curve. The total amount
of drug, through time, that has any activity when
administered orally.
§ AUCIV = Area under curve. The total amount of
drug, through time, that has any activity when
administered IV. This is the maximum amount of
drug that will have activity.
Ø
100% Bioavailability = A drug administered
by IV infusion.
ØBIOEQUIVALENCE: In order for two drugs to
be bioequivalent, they must have both the
same bioavailability and the same plasma
profile, i.e. the curve must have the same
shape. That means they must have the
same Cmax and Tmax.
ØCmax: The maximum plasma concentration
attained by a drug-administration.
v
Tmax: The time at which maximum
concentration is reached
v
REPETITIVE DOSES:
Ø
FLUCTUATIONS: Drug levels fluctuate as you
give each dose. Several factors determine
the degree to which drug levels fluctuate.
§ There are no fluctuations with continuous IV infusion.
§ Slow (more gradual) absorption also reduces
fluctuations, making it seem more like it were
continuous infusion.
§ The more frequent the dosing interval, the less the
fluctuations. Theoretically, if you give the drug,
say, once every 30 seconds, then it is almost like
continuous IV infusion and there are no
fluctuations.

Ø
Steady-State Concentration (CSS): The
plasma concentration of the drug once it
has reached steady state.
§ It takes 4 to 5 half-lives for a drug to reach the
steady state, regardless of dosage.
– After one half-life, you have attained 50% of CSS.
After two half-lives, you have attained 75%, etc.
Thus, after 4 or 5 half-lives, you have attained
~98% of CSS, which is close enough for
practical purposes.
§ If a drug is dosed at the same interval as its half-life,
then the CSS will be twice the C0 of the drug.
– If you have a drug of dose 50 mg and a half-life of
12 hrs, and you dose it every 12 hrs, then the
steady-state concentration you will achieve with
that drug will be 100 mg/L.

– D: Dose-amount. The higher the dose
amount, the higher the Css.
v
: Dosage interval. The shorter the dosage
interval, the higher the Css
– F: Availability Fraction. The higher the
availability fraction, the higher the Css.
– Kel: Elimination Constant. The higher the
elimination constant, the lower is the Css.
vVd: Volume of Distribution. A high volume of
distribution means we're putting the drug into a
large vessel, which means we should expect a
low Css.
– Cl: Clearance. The higher the drug-
clearance, the lower the Css.

– If you know the desired steady-state
concentration and the availability fraction,
then you can calculate the dosing rate.
vLOADING DOSE: When a drug has a long half-life,
this is a way to get to CSS much faster.
Ø Loading Dose = twice the regular dose, as long
as we are giving the drug at the same interval as
the half-life.
Ø
Ø
Ø
v
INTRAVENOUS INFUSION: The CSS is equal to the
input (infusion rate x volume of distribution)
divided by the output (Kel)

§ R0 = the rate of infusion.
§
Vd = the volume of distribution, which
should be equal to plasma volume, or
3.15L, or 4.5% of TBW.
§
Kel = Elimination Constant
v
Loading Dose in this case is just
equal to Volume of distribution time
vRENAL DISEASE: Renal disease means the drug is
not cleared as quickly ------> the drug will have
a higher Css ------> we should adjust the dose
downward to accommodate for the slower
clearance.
Ø If the fraction of renal clearance is 100% (i.e. the
drug is cleared only by the kidneys), then you
decrease the dosage by the same amount the
clearance is decreased.
§ For example: If you have only 60% of renal function
remaining, then you give only 60% of the original dose.
Ø If the fraction of renal clearance is less then 100%,
then multiply that fraction by the percent of renal
function remaining.
vFor example: If you have only 60% of renal
function remaining, and 30% of the drug is
cleared by the kidney, then the dose
adjustment = (60%)(30%) = 20%. The dose
should be adjusted 20%, or you should give
80% of the original dose
§ G = The percentage of the original dose that we
should give the patient.
v
If G = 60%, then we should give the
patient 60% of the original dose.
§ f = The fraction of the drug that is cleared by the
kidney.
v
If f is 100%, then the drug is cleared only
by the kidney.
§ ClCr = Creatinine clearance of patient, and normal
clearance. The ratio is the percent of normal
kidney function remaining.
Ø
Renal disease increases the time to reach
steady-state concentration. Renal Disease
------> longer half-life ------> longer time to
reach steady-state.

v