THE LADMER SYSTEM

I.

DRUG ADMINISTRATION
Often the goal is to attain a therapeutic drug concentration in plasma from which drug
enters the tissue (therapeutic window between toxic concentration and minimal effective
concentration).
A.

B.

Enteral Routes
1.

Sublingual (buccal)
Certain drugs are best given beneath the tongue or retained in the cheek
pouch and are absorbed from these regions into the local circulation.
These vascular areas are ideal for lipid-soluble drugs that would be
metabolized in the gut or liver, since the blood vessels in the mouth bypass
the liver (do not undergo first pass liver metabolism), and drain directly
into the systemic circulation. This route is usually reserved for nitrates
and certain hormones.

2.

Oral
By far the most common route. The passage of drug from the gut into the
blood is influenced by biologic and physicochemical factors (discussed in
detail below), and by the dosage form. For most drugs, two- to five-fold
differences in the rate or extent of gastrointestinal absorption can occur,
depending on the dosage form. These two characteristics, rate and
completeness of absorption, comprise bioavailability. Generally, the
bioavailability of oral drugs follows the order: solution > suspension >
capsule > tablet > coated tablet.

3.

Rectal
The administration of suppositories is usually reserved for situations in
which oral administration is difficult. This route is more frequently used
in small children. The rectum is devoid of villi, thus absorption is often
slow.

Parenteral Routes
1.

Intravenous injection
Used when a rapid clinical response is necessary, e.g., an acute asthmatic
episode. This route allows one to achieve relatively precise drug
concentrations in the plasma, since bioavailability is not a concern. Most
drugs should be injected over 1-2 minutes in order to prevent the
occurrence of very high drug concentrations in the injected vein, possibly
causing adverse effects. Some drugs, particularly those with narrow
therapeutic indices or short half-lives, are best administered as a slow IV
infusion or drip.

2.

Intra-arterial injection
Used in certain special situations, notably with anticancer drugs, in an
effort to deliver a high concentration of drug to a particular tissue.
Typically, the injected artery leads directly to the target organ.

3.

Intrathecal injection
The blood-brain barrier limits the entry of many drugs into cerebrospinal
fluid. Under some circumstances, usually life-threatening, antibiotics,
antifungals and anticancer drugs are given via lumbar puncture and
injection into the subarachnoid space.

4.

Intramuscular injection
Drugs may be injected into the arm (deltoid), thigh (vastus lateralis) or
buttocks (gluteus maximus). Because of differences in vascularity, the
rates of absorption differ, with arm > thigh > buttocks. Drug absorption
may be slow and erratic. The volume of injection, osmolality of the
solution, lipid solubility and degree of ionization influence absorption. It
should not be assumed that the IM route is as reliable as the IV route.

5.

Subcutaneous injection
Some drugs, notably insulin, are routinely administered SC. Drug
absorption is generally slower SC than IM, due to poorer vascularity.
Absorption can be facilitated by heat, massage or vasodilators. It can be
slowed by coadministration of vasoconstrictors, a practice commonly used
to prolong the local action of local anesthetics. As above, arm > thigh.

6.

Inhalation
Volatile anesthetics, as well as many drugs which affect pulmonary
function, are administered as aerosols. Other obvious examples include
nicotine and tetrahydrocannabinol (THC), which are absorbed following
inhalation of tobacco or marijuana smoke. The large alveolar area and
blood supply lead to rapid absorption into the blood. Drugs administered
via this route are not subject to first-pass liver metabolism.

7.

Topical application
a.
Eye
For desired local effects.
b.
Intravaginal
For infections or contraceptives.
c.
Intranasal
For alleviation of local symptoms.
d.
Skin
Topical drug administration for skin disorders minimizes systemic
exposure. However, systemic absorption does occur and varies
with the area, site, drug, and state of the skin. Dimethyl sulfoxide
(DMSO) enhances the percutaneous absorption of many drugs, but
its use is controversial because of concerns about its toxicity.
e.
Drug patches (drug enters systemic circulation by zero order
kinetics a constant amount of drug enters the circulation per unit
time).

II.

DRUG ABSORPTION
A.

Biologic Factors
1.

Membrane structure and function

The cell membrane is a semipermeable lipoid sieve containing numerous
aqueous channels, as well as a variety of specialized carrier molecules.
a.
For most tissues, passive aqueous diffusion through channels
occurs only for molecules less than 150-200 MW. A notable
exception is the endothelial capillary lining, whose relatively large
pores allow molecules of 20-30,000 to pass. However, the
capillaries of most of the brain lack these large pores.
b.
Passive lipid diffusion is probably the most important absorptive
mechanism. Lipid-soluble drugs dissolve in the membrane, and
are driven through by a concentration gradient across the
membrane.
c.
Carrier-mediated facilitated transport occurs for some drugs,
particularly those which are analogs of endogenous compounds for
which there already exist specific membrane carrier systems. For
example, methotrexate, an anticancer drug which is structurally
similar to folic acid, is actively transported by the folate membrane
transport system.

2.

Local blood flow is a strong determinant of the rate of absorption because

it continuously maintains the concentration gradient necessary for passive
diffusion to occur. For orally administered drugs, remember that the blood
supply draining the gut passes through the liver before reaching the
systemic circulation. Since the liver is a major site of drug metabolism,
this first-pass effect may reduce the amount of drug reaching the target
tissue. In some cases, the first-pass effect results in metabolic activation
of an inert pro-drug.

3.

Gastric emptying times vary among patients and contribute significantly to

intersubject variability in drug absorption.

4.

Drug binding
Many drugs will bind strongly to proteins in the blood or to food
substances in the gut. Binding to plasma proteins will increase the rate of
passive absorption by maintaining the concentration gradient of free drug.
For many drugs, the gastrointestinal absorption rate, but not the extent of
absorption, is reduced by the presence of food in the gut. Some drugs are
not affected by food, while the absorption of a third group of drugs is
enhanced by food (bile secretion by liver in response to food in GI tract
increases drug absorption). Some drugs are irritating and should be
administered with meals to reduce adverse effects.

B.

Physicochemical Factors: pH Partition Theory

1.

Background review
The simplest definition of an acid is that it is a substance, charged or
uncharged, that liberates hydrogen ions (H+) in solution. A base is a
substance that can bind H+ and remove them from solution. Strong acids,
strong bases, as well as strong electrolytes are essentially completely
ionized in aqueous solution. Weak acids and weak bases are only partially
ionized in aqueous solution and yield a mixture of the undissociated
compound and ions.
Thus a weak acid (HA) dissociates reversibly in water to produce
hydrogen ion H+ and A-.
HA <-----> H+ + A(1)
Applying the mass law equation, which demands that concentrations are in
moles per liter, we obtain the following equation:
[H+] [A-]
=
Ka
(2)
[HA]
where Ka is the ionization or dissociation constant of the acid. Since the
ion concentrations are in the numerator, the stronger the acid, the higher
the value of Ka. Similarly, one could derive Kb for a weak base BOH.
Rearranging equation (2) yields the following:
[H+] =
Ka [HA]
(3)
[A-]
Taking the log of both sides of the equation:
log [H+] = log Ka + log [HA] - log [A-]

(4)

And multiplying by -1, we obtain:

-log [H+] = -log Ka - log [HA] + log [A-]

(5)

By definition, -log [H+] = pH, and -log Ka = pKa. Thus, we obtain the
important relationships
for acids: pH = pKa + log [A-]
(6)
[HA]
for bases: pH = pKa + log [B]
(7)
[BH+]
From the pKa, one can calculate the proportions of drug in the charged
and uncharged forms at any pH:
log
[A-] = (pH - pKa)
(8)
[HA]
[A-] = 10(pH pKa)
(9)
[HA]
[B] = 10(pH-pKb)
(10)
[BH+]
pKb = (1-pKa)

2.

Ion trapping
The influence of pH on transfer of drugs across membranes.
What does this background review have to do with pharmacology. Plenty!
Most drugs are too large to pass through membrane channels and must
diffuse through the lipid portion of the cell membrane. Nonionized drug
molecules are readily lipid-soluble, while ionized molecules are
lipophobic and are insoluble.
The distribution of a drug across the cell membrane is usually determined
by its pKa and the pHs on both sides of a membrane. The difference of
pH across a membrane influences the total concentration of drug on either
side, since, by diffusion, at equilibrium the concentration of nonionized
drug will be the same on either side.
For example, let's consider the influence of pH on the distribution of a
drug which is a weak acid (pKa = 4.4) between plasma (pH = 7.4) and
gastric juice (pH = 1.4). The mucosa can be considered to be a simple
lipid barrier.

Figure 1

At equilibrium, the concentration of the unionized drug [HA] on either side of lipid barrier will
be the same. Using equation (9), we can calculate the molar ratios of ionized drug [A -] to [HA]
on each side of the membrane.
in plasma:
[A-]
[HA] = 10(7.4 - 4.4) = 103 = 1000
in gastric juice:
[A-]
[HA] = 10(1.4 - 4.4) = 10-3 = .001
Figure 2

The pKa values of certain acidic and basic drugs. Those drugs denoted with an * are
amphoteric. (From Rowland, M., and Tozer, T.N.)
III.

DRUG DISTRIBUTION
Once in the blood, drugs are simultaneously distributed throughout the body and
eliminated. Typically, distribution is much more rapid than elimination, is accomplished
via the circulation, and is influenced by regional blood flow.
A.

Compartments
1.

Central Compartment
The central compartment includes the well-perfused organs and tissues
(heart, blood, liver, brain and kidney) with which drug equilibrates rapidly.

2.

Peripheral Compartment(s)
The peripheral compartment(s) include(s) those organs (e.g., adipose and
skeletal muscle) which are less well-perfused, and with which drug
therefore equilibrates more slowly. Redistribution from one compartment
to another often alters the duration of effect at the target tissue. For
example, thiopental, a highly lipid-soluble drug, induces anesthesia within
seconds because of rapid equilibration between blood and brain. Despite
the fact that the drug is slowly metabolized, however, the duration of
anesthesia is short because of drug redistribution into adipose tissue,
which can act as a storage site, or drug reservoir.

3.

Special Compartments
Several special compartments deserve mention. Entry of drug into the
cerebrospinal fluid (CSF) and central nervous system (CNS) is restricted
by the structure of the capillaries and pericapillary glial cells (the choroid
plexus is an exception). The blood-brain barrier limits the success of
antibiotics, anticancer drugs and other agents used to treat CNS diseases.
Drugs also have relatively poor access to pericardial fluid, bronchial
secretions and fluid in the middle ear, thus making the treatment of
infections in these regions difficult.

B.

Protein Binding
Many drugs bind to plasma proteins. Weak acids and neutral drugs bind
particularly to albumin, while basic drugs tend to bind to alpha-1-acid
glycoprotein (orosomucoid). Some drugs even bind to red cell surface proteins.

C.

1.

Effects on drug distribution

Only that fraction of the plasma drug concentration which is freely
circulating (i.e., unbound) can penetrate cell membranes. Protein binding
thus decreases the net transfer of drug across membranes. Drug binding to
plasma proteins is generally weak and rapidly reversible, however, so that
protein-bound drug can be considered to be in a temporary storage
compartment. The protein concentration of extravascular fluids (e.g.,
CSF, lymph, synovial fluid) is very low. Thus, at equilibrium (when the
concentrations of free drug are equal), the total drug concentration in
plasma is usually higher than that in extravascular fluid. The extent of
protein binding must be considered in interpreting "blood levels" of drugs.

2.

Effects on drug elimination

The effects of plasma protein binding on drug elimination are complex.
For drugs excreted only by renal glomerular filtration, protein binding
decreases the rate of elimination since only the free drug is filtered. For
example, the rates of renal excretion of several tetracyclines are inversely
related to their extent of plasma protein binding. Conversely, however, if
drug is eliminated by hepatic metabolism or renal tubular secretion,
plasma protein binding may promote drug elimination by increasing the
rate that that drug is presented for elimination.

3.

Tissue binding
Binding to tissue proteins may cause local concentration of drug. For
example, if a drug is bound more extensively at intracellular than at
extracellular sites, the intracellular and extracellular concentrations of free
drug may be equal or nearly so, but the total intracellular drug
concentration may be much greater than the total extracellular
concentration.

Apparent volume of distribution (AVD or Vd).

The volume of distribution, or more properly the apparent volume of distribution,
is calculated from measurements of the total concentration of drug in the blood
compartment after a single IV injection. Suppose that we injected someone IV
with 100 mg of a drug, and measured the blood concentration of the drug
repeatedly during the next several hours. We then plot the blood concentrations
(on a log scale) against time, and obtain the following graph:

Figure 3

If the drug is assumed to follow two-compartment kinetics, the initial curvilinear portion
of the data reflects the drug distribution phase, with drug moving from the blood into
tissues. The linear portion of the curve reflects drug elimination. By extrapolation of the
linear portion, we can find the blood concentration at time 0, had mixing between both
compartments been instantaneous; it is 10 mg/ml. We can also calculate V d, which is
defined as:
Vd = amount of drug injected
blood concentration at time 0

100 mg = 10L
10 mg/L

Vd does not represent a real volume, but rather indicates the size of the pool of body
fluids that would be required if the drug were distributed equally throughout the body.
Drug concentrations in body compartments will vary according to the physicochemical
properties of the drug. Thus, Vd is a characteristic property of the drug rather than the
patient, although disease states may influence Vd. If binding to plasma proteins is
marked, most of the drug will be maintained within the intravascular compartment and
Vd will be small. If there is extravascular binding, or storage in fat or other tissues, V d
will be large. For example, digoxin, a hydrophobic drug which distributes into fat and
muscle, has a Vd of 640 liters (in a 70 kg man), approximately nine times the total
volume of the man! The usefulness of the V d concept will become more apparent when
we discuss pharmacokinetics and perform calculations of blood levels of drugs.
In general, acidic drugs bind to plasma proteins and have small Vds, while basic drugs
tend to bind more extensively to extravascular sites and have larger Vds. Vd may be
influenced by disease states. For example, patients with chronic liver disease have lower
serum albumin concentrations. Plasma protein binding will be reduced, leading to lower
plasma drug concentrations and higher Vds.
IV.

DRUG BIOTRANSFORMATION
The body is exposed to a wide variety of foreign compounds, called xenobiotics.
Exposure to some such compounds is unintentional (e.g., environmental or food
substances), while others are deliberately used as drugs. The following discussion of
drug biotransformation is applicable to all xenobiotics, and to some endogenous
compounds (e.g., steroids) as well.
The kidneys are capable of eliminating drugs which are low in molecular weight, or
which are polar and fully ionized at physiologic pH. Most drugs do not fit these criteria,
but rather are fairly large, unionized or partially ionized, lipophilic molecules. The
general goal of drug metabolism is to transform such compounds into more polar (i.e.,
more readily excretable) water soluble products. For example, were it not for

biotransformation to more water-soluble products, thiopental, a short-acting, lipophilic

anesthetic, would have a half-life of more than 100 years! Imagine, without
biotransformation reactions, anesthesiologists might grow old waiting for patients to
wake up.Most products of drug metabolism are less active than the parent compound. In
some cases, however, metabolites may be responsible for toxic, mutagenic, teratogenic or
carcinogenic effects. For example, overdoses of acetaminophen owe their hepatotoxicity
to a minor metabolite which reacts with liver proteins. In some cases, with metabolism
of so-called prodrugs, metabolites are actually the active therapeutic compounds. The
best example of a prodrug is cyclophosphamide, an inert compound which is metabolized
by the liver into a highly active anticancer drug.
A.

Sites of drug metabolism

1.

At the organ level

The liver is the primary organ of drug metabolism. The gastrointestinal
tract is the most important extrahepatic site. Some orally administered
drugs (e.g., isoproterenol) are conjugated extensively in the intestinal
epithelium, resulting in decreased bioavailability. The lung, kidney,
intestine, skin and placenta can also carry out drug metabolizing reactions.
Because of its enormous perfusion rate and its anatomic location with
regard to the circulatory system, the lungs may exert a first-pass effect for
drugs administered IV.

2.

At the cellular level

Most enzymes involved in drug metabolism are located within the
lipophilic membranes of the smooth endoplasmic reticulum (SER). When
the SER is isolated in the laboratory by tissue homogenation and
centrifugation, the SER membranes re-form into vesicles called
microsomes. Since most of the enzymes carry out oxidation reactions, this
SER complex is referred to as the microsomal mixed function oxidase
(MFO) system.

3.

At the biochemical level

Phase I reactions refer to those which convert a drug to a more polar
compound by introducing or unmasking polar functional groups such as
-OH, -NH2, or -SH. Some Phase I products are still not eliminated
rapidly, and hence undergo Phase II reactions involving conjugation of the
newly established polar group with endogenous compounds such as
glucuronic acid, sulfuric acid, acetic acid, or amino acids (typically
glycine). Glucuronide formation is the most common phase II reaction.
Sometimes, the parent drug may undergo phase II conjugation directly. In
some cases, a drug may undergo a series of consecutive reactions resulting
in the formation of dozens of metabolites.
Most phase I MFO biotransformation reactions are oxidative in nature and
require a reducing agent (NADPH), molecular oxygen, and a complex of
microsomal enzymes; the terminal oxidizing enzyme is called cytochrome
P450, a hemoprotein so named because its carbon monoxide derivative
absorbs light at 450 nm. We now know that cytochrome P 450 is actually a
family of enzymes which differ primarily with regard to their substrate
specificities. Advances in molecular biology have led to the identification
of more than 70 distinct P450 genes in various species.
The nomenclature of the P450 reductase gene products has become
complex. Based upon their amino acid homologies, the P 450 reductases
have been grouped into families such that a cytochrome P 450 from one
family exhibits < 40% amino acid sequence identity to a cytochrome P 450

in another gene family. Several of the gene families are further divided
into subfamilies, denoted by letters A, B, C, etc.

V.

B.

Enzyme Induction
An interesting and important feature of the cytochrome P 450 mixed function
oxidase system is the ability of some xenobiotics to induce the synthesis of new
enzyme. Microsomal enzyme induction is a complex and poorly understood
process associated with an increase in liver weight, proliferation of the SER, and
synthesis of P450 enzymes. For example, phenobarbital induces the P450IIB
subfamily, while polycyclic aromatic hydrocarbons (e.g., found in cigarette smoke
or charcoal broiled foods) induce the P450IA subfamily; these and other inducers a
Obviously, the dose and frequency of drug administration required to achieve
therapeutic drug concentrations in blood may vary enormously from person to
person, depending upon the degree of exposure to microsomal inducers.For
example, consider patients who routinely ingest barbiturates or tranquilizers (P 450
inducers) who must, for medical reasons, be treated with warfarin or dicumarol
(oral anticoagulants). Because of a faster rate of drug metabolism, the dose of
warfarin will need to be high. If the patient should for some reason discontinue
the barbiturates, the blood level of warfarin will rise, perhaps leading to a
bleeding disorder.

C.

Enzyme Inhibition
Relatively few xenobiotics are known to inhibit microsomal enzymes. Some
drugs are used therapeutically because they inhibit specific enzyme systems (e.g.,
monoamine oxidase inhibitors for depression, xanthine oxidase inhibitors for
gout, etc.). Sometimes such drugs are not totally specific and inhibit other
enzyme systems to some extent. However, cimetidine, a widely used anti-ulcer
drug, is an important, potent inhibitor of microsomal drug metabolism which
retards the metabolism of many other drugs, including warfarin and similar
anticoagulants, theophylline and caffeine, phenobarbital, phenytoin, carbamazepine, propranolol, diazepam, and chlordiazepoxide. Other inhibitors are
erythromycin and ketonazole. You will encounter these drugs later in the course.
Grapefruit juice also inhibits cytochrome.

DRUG ELIMINATION
The kidney is the most important organ for the excretion of drugs and/or their
metabolites. Some compounds are also excreted via bile, sweat, saliva, exhaled air, or
milk, the latter a possible source of unwanted exposure in nursing infants. Drug
excretion may involve one or more of the following processes.
A.

Renal Glomerular Filtration

Glomeruli permit the passage of most drug molecules, but restrict the passage of
protein-bound drugs. Changes in glomerular filtration rate affect the rate of
elimination of drugs which are primarily eliminated by filtration (e.g., digoxin,
kanamycin).

B.

Renal Tubular Secretion

The kidney can actively transport some drugs (e.g., dicloxacillin) against a
concentration gradient, even if the drugs are protein-bound. (Actually, only free
drug is transported, but the protein-drug complex rapidly dissociates.) A drug
called probenecid competitively inhibits the tubular secretion of the penicillins,
and may be used clinically to prolong the duration of effect of the penicillins.

C.

Renal Tubular Reabsorption

Many drugs are passively reabsorbed in the distal renal tubules. Reabsorption is
influenced by the same physicochemical factors that influence gastrointestinal

absorption: nonionized, lipid-soluble drugs are extensively reabsorbed into

plasma, while ionized and polar molecules will remain in the renal filtrate and be
excreted via urine. Thus, as in the gut, urine pH plays an important role, as does
urine volume. Urine pH may vary widely from 4.5 to 8.0, may be influenced by
diet, exercise, or disease, and tends to be lower during the day than at night. It is
sometimes clinically useful, particularly in drug overdose cases, to alter the pH of
the urine (of the patient). For drugs which are weak acids, urine alkalinization
favors the ionized form and promotes excretion. Alternatively, acidification
promotes the renal clearance of weak bases.
D.

Biliary Excretion
Comparatively little is known about hepatic drug elimination. Many drugs and
metabolites are passed into the small intestine via bile and may undergo
enterohepatic cycling. Recent studies have attempted to interrupt enterohepatic
cycling of drugs, pesticides and heavy metals through the oral administration of
non-absorbable, nonspecific adsorbents such as charcoal or cholestyramine. The
results, generally a decrease in drug half-life, have been surprising in that they
suggest that many more drugs undergo enterohepatic cycling than previously
suspected