Unit III: How drugs work
the most fundamental concepts in pharmacology is that of molecule-receptor
interactions. Receptors are specialized molecular binding sites where
substances, like neurotransmitters, dock thereby producing physiologic effects.
Most receptors are large proteins that span the cellular membrane, thus having
three portions: one on the exterior of the cell where molecules bind; in the
cell’s interior that subsequently initiate intracellular biochemical reactions,
and a trans-membrane portion, which among other things helps to keep the
receptor in place. This concept applies not only to the action of naturally
occurring or endogenous substances such as neurotransmitters and hormones, but
also to exogenous substances like drugs. Many drugs mimic the effects of
hormones and neurotransmitters because they bind with the same receptors as
these endogenous substances do. Hence, most drugs don’t do anything completely
new to the body. Rather they mimic or influence naturally occurring processes.
can mimic a neurotransmitter or hormone. If the drug produces an effect to the
same extent as the natural occurring molecule it is called a full agonist. If
it produces the same general response but to a lesser effect than the
endogenous substance it is a partial agonist. If a drug augments or facilitates
an endogenous compound’s effects without actually binding to the natural
substance’s receptor it is referred to as an indirect agonist.
can prevent endogenous compounds from binding to their receptors by occupying
the receptor without producing a physiologic response. Such drugs are referred
to as antagonists. As is the case with agonists, if a drug diminishes or
prevents an endogenous compounds effects without actually binding to the
natural substance’s receptor it is referred to as an indirect antagonist.
can bind to a receptor and provoke an action opposite to that of the endogenous
substance. Such drugs are called inverse agonists. Just like there are full and
partial agonists, there are full and partial inverse agonists, too.
can inhibit enzymes form performing their physiologic activities or they can
activate enzymes so that they become more active than usual. For example, a
drug can inhibit an enzyme that is necessary to deactivate a neurotransmitter
thereby increasing or prolonging its activity (e.g. such as a MAO-I). Drugs can
also block transporters or reuptake pumps that usually operate to recycle
neurotransmitters. Drugs can cause more or less neurotransmitter to be released
from axon terminals through various actions such as causing more vesicles to
release their contents upon depolarization or by causing the vesicles
themselves to become leaky thus depleting their contents. Drugs can influence
the degree that ion channels open or close in the cell membranes.
drugs have multiple actions that produce not just the desirable therapeutic
effect, but side effects as well. For example, the tricyclic antidepressant
amitriptyline (Elavil) acts as an indirect agonist for the neurotransmitter
norepinephrine, and serotonin to a lesser extent, by blocking their neuronal
reuptake pumps (its postulated mechanism of therapeutic action). At the same
time, it acts as an acetylcholine antagonist by occupying the acetylcholine
receptor thus blocking the action of acetylcholine at its binding site (causing
the so-called anticholinergic side-effects such as dry mouth and constipation).
In addition, amitriptyline inhibits sodium ion channels which results in slowed
depolarization especially in the cardiac muscle (causing this medicine to be
prescribed with great caution to patients with any compromised cardiac
is the study and description of the rate and extent of absorption,
distribution, metabolization, and elimination of drugs in the body. In simple
terms, pharmacokinetics is what the body does to a drug once it is
administered. Hence, the four phases of pharmacokinetics (e.g., absorption,
distribution, metabolization, and elimination) are often depicted by the
acronym ADME. (Sometimes, the term biotransformation is used synonymously with
metabolization, rendering the alternative acronym ADBE. Similarly, some people
refer to the final phase as excretion rather than elimination, but, of course,
this doesn’t change the acronyms.)
involves the passage of the drug from its site of administration into the
blood. Obviously, for a drug to have any effect it must be absorbed into the
system. Usually, drugs are taken orally (i.e., po from the Latin per os which
means literally by or through the mouth) and most absorption, therefore, takes
place in the gastrointestinal tract, chiefly in the duodenum and proximal
jejunum, the first few feet of the small intestine. While there are several
other routes of administration, the vast majority of psychotropics is taken by
mouth and most of the examples in this section assume the oral route of
administration. Other ways through which drugs can enter the body are through
the skin by topical preparations or transdermal patches, subcutaneously (under
the skin), intramuscularly or intravenously via injection, rectally or
vaginally with suppositories, in the eye or ear with drops, and even through
inhalation as with gases. Generally, the terms take, apply, insert, and place
refer to the oral, topical, rectal/vaginal, and eye/ear routes, respectively.
One additional route is sublingual which refers to placing the drug under the
tongue. This circumvents the gastrointestinal tract by allowing the drug to be
absorbed directly into venous circulation through the capillary bed at the base
of the tongue, which can have some important benefits.
which are taken by mouth are absorbed in the stomach and small intestine. In
much the same way that nutrients are absorbed into the blood stream, drugs
enter circulation by absorption into the venous blood supply of the digestive
tract. This means that the drug must pass through several biological membranes
before it can enter circulation such as the membranes of the cells lining the
stomach and intestines, and the membranes of the blood vessels into which the
drug need enter. Broadly speaking, there are two mechanisms by which molecules
can cross cell membranes: passive processes where the driving force is a
concentration gradient, and active transport which requires the expenditure of
cellular energy and can drive molecules against concentration gradients.
most common passive ways that a drug can cross a cellular membrane include
diffusion (i.e., the random movement of molecules from an area of high
concentration to low concentration), filtration (i.e., movement of molecules
through pores in the membrane), and facilitated diffusion (i.e., when a
substance temporarily binds to a specific carrier molecule that ferries it
across the membrane). Active transport is the energy-dependent movement of
molecules across membranes, usually against their concentration gradient. In
active transport, as with facilitated diffusion, the substance to be
transported reversibly binds to a carrier molecule (usually a protein) that
conveys it across the membrane. In general, drugs will not be actively
transported unless they very closely resemble the endogenous substances (such
as glucose and amino acids) that are the normal passengers for the carrier
system involved. For this reason, most drugs are absorbed from the intestinal tract
through passive processes, and involve mostly diffusion.
are many factors that can influence the degree to which a drug is absorbed, but
most of these can be grouped into two categories: the physiochemical (i.e.,
relating to the physical and chemical) properties of the drug, and patient
variables. Physiochemical properties include factors such as the drug’s
dissolvability, its solubility in fat (lipophilicity) versus water
(hydrophilicity), whether it is an acid or a base, and its molecular size, to
name only a few. Patient variables include whether the drug is taken with food
or on an empty stomach, as well as a variety of other factors including the
patient’s age, weight, gender, and general health.
involves the processes through which the drug, once absorbed, is delivered to
the tissues and eventually to its sites of action. The system responsible for
this phase of pharmacokinetics is the circulatory system which delivers drugs
and other materials to the furthest outposts of the body. Once absorbed into
the blood supply of the digestive tract, a drug is considered to be in general
or systemic circulation. Before it can be delivered to its site of action,
usually the CNS in the case of psychotropics, it will journey through a
consistent passage of blood vessels. Substances that are absorbed into the
blood supply from the digestive system enter into small veins called venules
which along with tiny arteries called arterioles make up the capillary beds. In
addition to absorbing nutrients and drugs, capillary beds deliver fresh,
oxygenated blood to organs and remove waste products from them. Venous blood
from the digestive tract eventually makes it way to the heart where it is
pumped to the lungs for oxygenation (and to remove gaseous waste, mostly carbon
dioxide), then returned to the heart from where it enters systemic circulation.
As a general rule, veins convey deoxygenated blood to the heart, arteries
transport oxygenated blood from the heart. (An exception to this is in adult
cardiopulmonary circulation where arteries carry deoxygenated blood from the
heart to the lungs, and veins return it, once oxygenated, to the heart for
pumping to the rest of the body.)
drug proceeds to its ultimate destination, it encounters many barriers it must
cross before it reaches its site of action. In much the same way that the drug
had to pass through various biological membranes to enter the blood stream, it
must similarly cross various membranes to reach its site of action. One important
obstacle most centrally acting drugs must surmount is the blood-brain barrier
(BBB) which insulates and protects the CNS from toxins by allowing only certain
molecules to enter the brain. Most psychotropics are fat-soluble compounds and
since the BBB preferentially allows fat-soluble substances to pass, as a
general rule psychotropics have little difficulty entering the CNS.
distribution of a medication throughout the body is a two-phase process.
Initially, most of the drug is delivered to the organs which have the richest
supply of blood, such as the liver, heart, lungs, kidneys, and brain.
Subsequently, the drug moves into the tissues which have less extensive
perfusion such as muscles, fat, and bone. These latter areas of the body are referred
to as reservoirs or compartments in which drugs can accumulate.
example, some psychotropics do not distribute uniformly throughout the body
because of their affinity for muscle and fat cells. After chronic
administration, significant concentrations of drug can accumulate in these
reservoirs which has obvious implications when the drug is discontinued, since
it can leach out of these compartments thus prolonging the biological life of
the drug in the system. While this can be problematic in some cases, this
phenomenon also has important therapeutic utility in that some drugs can be
delivered to these reservoirs deliberately to allow for sustained therapeutic
action. For example, some antipsychotic agents (e.g., Prolixin and Haldol) can
be administered by injection once every several weeks which greatly improves
patient compliance due to ease of dosing and consistent drug effects.
important mechanism through which drugs can be compartmentalized in the body
involves the binding of drugs to plasma proteins. Blood plasma is the fluid
(noncellular) portion of circulating blood and has a great many substances
dissolved in it such as electrolytes, sugars, hormones, and proteins. One of
the most common proteins in blood plasma is albumin. Although some drugs are
simply dissolved in the blood fluid, most are associated with plasma proteins
like albumin to which they bind, partly irreversibly. Remember that the
receptors to which neurotransmitters bind are large proteins into which the
neurotransmitter fits like a key into a lock. Also, recall that many drugs act
by binding to these same receptors. Plasma proteins are very similar in
structure to receptors. Hence it is not surprising that many drugs bind to the
plasma proteins in much the same way that they couple with receptors. The
extent of this binding will significantly influence the drug’s distribution,
concentration at effectors (i.e., sites of action), and rate of metabolization
and elimination because only the unbound drug can diffuse through membranes.
Thus, only the unbound fraction of the drug is biologically active.
Furthermore, extensive protein binding results in the blood’s serving as a
circulating drug reservoir. As free or unbound drug is eliminated from the
body, more drug dissociates from the plasma proteins to replace the unbound
drug that was lost. Therefore, extensive protein binding can prolong drug
availability and duration of action.
additional important phenomenon that warrants mention is displacement of drug
from plasma proteins. The binding of drugs to plasma proteins is usually
nonspecific which means that many different drugs can interact with the same
binding site. A drug with a higher affinity for the protein’s binding site may
displace a drug with a weaker affinity from it. Obviously, since only the
unbound portion of a drug is biologically active, this can have profound
pharmacologic and clinical implications. For example, if drug B displaces a
significant amount of drug A from its protein binding sites, there will be more
free drug A available to cross cell membranes which will result in a greater
concentration at its site of action and an intensified pharmacologic effect.
blood form the gastrointestinal system reaches the heart, and enters systemic
circulation, it first passes through the liver which is the major organ of
metabolization or biotransformation. Although it is a gross simplification, the
liver can be likened to a biochemical processing plant that modifies substances
passing through it. Indeed, the liver contains an enormous amount and variety
of enzymes that act as molecular processors, ultimately changing or
transforming the biological substances that encounter them. This is why the
term biotransformation is synonymous with metabolization because through the
metabolic action of it’s enzymes, the liver biologically transforms molecules
from their original form, the parent compound, to new products called
major drug metabolizing enzymes of the liver are often called the cytochrome
(CYP) 450 system and include more than 30 related enzymes. These enzymes, which
evolved over 1 billion years ago during the era of plant-animal
differentiation, have the ability to metabolize foreign biological substances.
These enzymes allowed the animals that possessed them to metabolize plant
toxins before they could enter the animal’s systemic circulation thus
protecting them from harm. Obviously, such a system would confer tremendous
survival advantages and be passed on to future generations and new species.
Since many drugs originally come from plant products, and resemble plant
toxins, they are readily metabolized by this same system of enzymes. In
addition to providing protection form toxicity, these enzymes serve to
transform substances into forms that can be readily eliminated form the body.
Indeed, these enzymes determine in part what compounds can become drugs because
if a mechanism did not exist to eliminate a substance from the body it could
not be [safely] used as a drug.
activities of the CYP 450 enzymes are variable. Basically, their numbers and
activity can be increased (enzyme induction) or decreased (enzyme inhibition)
through the actions of drugs and their metabolites. Although the analogy is not
precise, these phenomena can be thought of as similar to the agonist and
antagonist effects that drugs produce at receptors which in may cases resemble
the enzymes structurally. For example, the anti-epileptic and mood stabilizing
agent carbamazepine (Tegratol) induces certain enzymes which can cause a
reduction in a drug’s bioavailability if that drug is metabolized by the
enzymes that Tegratol induces. Alternatively, the SSRI fluvoxemine (Luvox) is a
potent inhibitor of the enzyme that metabolizes the antianxiety agent
alprzaolam (Xanax). Therefore, if Luvox and Xanax are co-administered, the
effects of the Xanax can be significantly amplified because of Luvox’s
inhibitory effect on the enzyme that Xanax depends on for its biotransformation
and eventual elimination from the body. Other factors, such as smoking and
liver disease, respectively, can induce or inhibit many of the CYP 450 enzymes
thus influencing the metabolization of many drugs.
important aspect of metabolization is the so-called first-pass effect which
simply refers to the fact that drugs absorbed into the blood stream from the
digestive tract first pass through the liver before entering systemic
circulation. On this pass through the liver, drugs can undergo extensive metabolization
by the CYP 450 system and other enzymes present in the liver. On the one hand,
this phenomenon can significantly reduce the concentration of many drugs
resulting in a diminished therapeutic effect. On the other hand, some drugs
(called prodrugs) must first be metabolized before they become biologically
active. For example, the benzodiazepine clorazepate (Tranxene) is an inactive
prodrug which becomes the active compound desmethyldiazepam once it has been
metabolized by liver enzymes. Parenteral drug administration (i.e., in a manner
other than through the digestive tract such as by injection, topical, rectal,
vaginal, or sublingual routes) circumvents the first-pass effect.
important to note that some metabolites are more pharmacologically active than
the parent drug. For example, Prozac (fluoxetine) is metabolized into a form,
norfluoxetine, that is believed to be more potent than Prozac at inhibiting the
serotonin reuptake pump. In addition, some metabolites are more potent enzyme
inhibitors than their parent drugs and/or have much longer half-lives (the
amount of time it takes to eliminate one-half of the substance from the body)
or biological activity.
have discussed, the biological activity of a drug depends on many processes. To
completely terminate the pharmacological effects of a drug, it must be
eliminated from the body. Indeed, in addition to detoxifying substances, the
process of metabolization also prepares them for removal from the body by
transforming them into metabolites that are more readily excreted than the
original compound. Excretion is the process whereby substances are moved to the
outside of the body. Several systems participate in drug elimination, such as
the lungs through exhalation, the gastrointestinal tract through defecation,
and the skin through perspiration. As important as these routes of elimination
are, by far the most import organ of drug elimination is the kidney which
excretes drug metabolites through urine. Indeed, the kidney filters almost two
thousand liters of blood a day (about 475 gallons) to produce a mere liter of
this amount is sufficient to eliminate the vast majority of drugs and other
metabolic waste products from the body. It is important to consider that the
physiochemical properties of a drug that govern its absorption by crossing
several biological barriers also apply to drug excretion. For example, the
urinary elimination of drugs can be influenced by modifying the acidity or
alkalinity of the urine. Basically, increasing the acidity of urine hastens the
elimination of basic substances while increasing its alkalinity speeds up
excretion of acidic compounds.
drug that influences one or more phases of pharmacokinetics can result in a
drug-drug interaction that may intensify or diminish the therapeutic effects.
For example, antacids are know to interfere with benzodiazepine absorption thus
diminishing their therapeutic onset. Displacement from plasma proteins of one
drug by another can significantly increase the bioavailability of the displaced
drug resulting in a greater therapeutic effect (or even toxicity) than would be
predicted based on the original dose of the displaced drug. This would be an
example of a pharmacokinetic drug-drug interaction involving the distribution
phase. We have already provided an example of a pharmacokinetic interaction
involving metabolization, i.e., Luvox inhibiting one of the enzymes Xanax
depends on for its biotransformation, thus intensifying or prolonging its
effects. Moreover, the fact that certain drugs can change the acidity of urine
can influence the rate of another drug’s elimination from the body.
provided a general overview of some of the most fundamental pharmacokinetic
processes (what the body does to the drug), we will now turn our attention to
what the drug does to the body, or what is often called pharmacodynamics.
its absorption and distribution to its sites of action, a drug will produce
physiological effects that ultimately result in a therapeutic response. With
psychotropic medications, the major organ effected is the brain. In most cases,
psychotropics produce their therapeutic effects by binding to specific
receptors or enzymes. Ultimately, psychotropics produce therapeutic effects by
changing neural activity which is a consequence of effecting the traffic
patterns of neurotransmitters or in some cases intracellular, second-messenger
general terms, drugs produce both acute effects, and long-term compensatory changes
in the flow of neurotransmitters and cellular activity. Acute effects are the
rapid changes in neurotransmitter concentrations that follow within minutes or
hours of a drug’s administration. Long-term compensatory effects refer to
certain adaptations that neurons undergo after chronic administration of a
drug. Usually these adaptations involve modifying the population of receptors;
a genetically mediated process that requires the cell to synthesize and insert
into its membrane new numbers of receptor molecules. These adaptations, which
compensate for the change in neurotransmitter traffic, are often referred to as
receptor down-regulation or up-regulation depending on whether the end result
is that the cell has less receptors (down regulation) or more (up regulation).
These phenomena, also called neural plasticity, take up to several weeks to
occur. This time frame is highly correlated with the therapeutic onset of many
psychotropics, leading to the generally accepted hypothesis that their
therapeutic effects result from these compensatory adaptations. Similarly, the
reversal of these adaptations, upon discontinuation of the drug, can take
several weeks to occur thus explaining why relapse is often delayed in much the
same way as response lags behind initiation of the drug. Some psychotropics,
however, such as the benzodiazepines, act therapeutically by producing
short-term effects. Hence, these drugs work relatively quickly and only while
present at the receptors where they exert their influence.
pharmacodynamic processes involve drug effects at receptors. Just as there are
many pharmacokinetically mediated drug-drug interactions, there are also many
important pharmacodynamically mediated drug-drug interactions. In essence, any
drug that influences another drug at its receptors or sites of action will
produce pharmacodynamic interaction that will either potentiate or attenuate
their pharmacologic effects. For example, tricyclic antidepressants have
effects at several types of receptors. Hence they often potentiate
antihistamines (due to their effects at histamine receptors), several
antihypertensives (due to their effects at the alpha-1 adrenergic receptor),
anticholinergic agents (due to their blockade of muscarinic cholinergic
receptors), and certain antiarrhythmics (due to their direct membrane
additional terms and concepts that are important include efficacy, potency,
toxicity, and therapeutic index. Efficacy refers to the capacity of a drug to
produce a desired result or effect and can be thought of synonymous with
effectiveness. If drug A (morphine) is capable of relieving more pain that drug
B (ibuprofen), drug A is said to have greater analgesic efficacy that Drug B.
Hence even at high doses, ibuprofen cannot match morphine’s analgesic
effectiveness. Potency concerns the dosage of a drug needed to produce a
therapeutic effect. If less of drug A is needed to produce a given response
than drug B, drug A is more potent than drug B. For example, since 200 mg of ibuprofen
is able to produce the same amount of pain relief as 500 mg of acetaminophen,
ibuprofen is more potent that acetaminophen. Interestingly, just because one
drug is more potent than another doesn’t mean it’s necessarily more
efficacious. For example, both alprazolam (Xanax) and diazepam (Valium) are
equally efficacious in reducing anxiety, but alprazolam is about ten times as
potent as diazepam. Thus 1 mg of alprazolam has about the same efficacy as 10
mg of diazepam.
refers to a substance’s potential for producing harm to one or more biological
systems that if seriously damaged can result in injury or death. Toxicity and
lethality are directly and positively correlated so that the more toxic a
substance is the greater its lethality. A critical parameter that directs safe
and effective drug use is the therapeutic index which is a quantitative
comparison of a drug’s effective concentration (efficacy) and its toxic
concentration (toxicity). The closer together these two measurements are, the
narrower the index, and therefore the less safe the drug. In
psychopharmacology, lithium and tricyclic compounds have small therapeutic
indices (and are therefore more dangerous) than benzodiazepines and SSRIs which
have large therapeutic indices.
drug forms include liquids, tablets, and capsules. Liquid dosage forms have the
fastest absorption rate. Tablets are absorbed more slowly. Capsules are often
formulated as time-release or sustained-release products and have the advantage
of requiring fewer daily doses.
variety of problems may occur with oral drug administration, including stomach
and intestinal problems.
administration is the slowest method of absorption, and the onset of a drug's
effect is less predictable because drug absorption from the gastro-intestinal
tract is often erratic.
that affect the rate of absorption of a drug are related to the concurrent
intake of food and the drug's pH (acidity or basicity) relative to the pH
values of the stomach and the intestines. Drugs can exist in two
interconvertible forms, a water-soluble or ionized form and a lipid-soluble or
less ionized form.
drug's lipid-to-water solubility is primarily determined by the pH of the drug
relative to the pH of the body fluid that harbors the drug.
administered orally undergo a process called first-pass metabolism, which
occurs immediately after the drug is absorbed from the gastrointestinal tract.
The blood carries the drug to the liver, where some of the drug is metab-olized
and thus rendered inactive or unable to exert its desired effect.
basic methods are used for injecting medication: intravenous, intramus-cular,
and subcutaneous injections. Intravenous (into the vein) injection has the
fastest absorption rate. Because of this, it is potentially the most dangerous
form for injection of medication. Intramuscular (into the muscle) injection
provides a means for rapid absorption but is not as fast as intravenous injection
(e.g., antibiotics). Subcutaneous (under a layer of skin) is used when a slower
and more constant rate of absorption is recommended (e.g., insulin).
injectable antipsychotics, such as Haldol Decanoate and Prolixin Decanoate are
formulated to prolong the effects of the drug. Effects of both of these
injectable drugs can last three to four weeks.
METHODS OF MEDICATION ADMTNISTRATTON
variety of other methods are used for administering drugs, including sublingual
(a tablet placed under the tongue) and buccal (drug positioned between cheek
and gum). In each of these alternate administration methods, a drug is readily
absorbed into the bloodstream because of the highly vascular membranes (high
number of blood vessels) in each of these areas.
administered and absorbed in the bloodstream, medications are carried to
various body tissues via the circulatory system. Blood capillaries deliver
drugs to different areas in the body. For most drugs, capillary pores are large
enough to allow free passage for the drugs to exit the blood system and exert
drugs bind irreversibly to circulating proteins in the plasma or blood. A drug
that becomes protein-bound is usually so large that it is unable to exit the capillary,
rendering it inactive in the bloodstream until separation from the protein.
Drug protein binding also hinders a drug's metabolism and excretion, thus
causing a drug to remain in the body longer, which increases the drug's
term half-life refers to the amount of time (usually given in hours) that is
required for half of the active part of the drug to be eliminated from the body
after discontinuation. Usually, it takes about 5 or 6 half lives for most of
the drug to be eliminated. Drugs with a short half-life (e.g., Ritalin), must
be dosed multiple times per day (TID or QID). Drugs with a long half-life may
be dosed only once per day, but may be dangerous with overdose because it will
take a lot longer for the drug to be eliminated (for example, the sleep
medication Dalmane, which has a half-life of about 200 hours).
drug's passage across various membranes or barriers in the body, such as the
stomach, intestines, blood-brain barrier (BBB), and placenta, depends on a
drug's lipid (fat) solubility. Drugs with a high lipid solubility cross the BBB
easily and remain in the brain tissues longer than water-soluble drugs do. This
difference is explained by the fact that lipid-soluble chemicals or drugs are
stored in the body's fat tissue. Unlike many categories of medication,
psychotropic medications and drugs of abuse can cross the BBB and reach the
central nervous system rather easily.
drugs are metabolized or broken down in the body by liver enzymes, which act to
transform chemicals or drugs into more water-soluble (or hydrophilic) entities
so the drugs can be excreted in the urine. Because of the decline in liver
activity among the elderly, it takes them longer to metabolize drugs. Therefore,
drug dosages for the geriatric population are usually reduced. Risks of
overmedicating are also of particular concern among persons with heart, liver,
and kidney disease.
kidney is the body's main excretory organ. Therefore, a client with kidney
problems may accumulate more drugs in the body, thus requiring smaller doses.
Less frequently, drugs are eliminated from the body via the lungs, sweat
glands, saliva, feces, bile, and breast milk.
EFFECTS, INTERACTIONS, CONTRAINDICATIONS, AND TOXICITY MEDICATION SIDE EFFECTS
terms used to describe drug side effects are adverse reactions and untoward or
unwanted effects. Rather than being selectively carried to a specific or
targeted area, drugs are widely distributed throughout the body. Therefore, a
drug will bind with any receptor that its chemical structure will allow. This
nonselective drug-binding capacity explains the origin of drug side effects.
Adverse drug side effects must be monitored, and a drug's benefits should
outweigh any detrimental side effects (often as the dosage is increased).
Due to the necessity of monitoring adverse effects,
various amounts of testing may be required and can include blood testing,
pharmacogenetic testing, and urine testing.
Agonists and Antagonists
that increases the availability or mimics the action of an endogenous NT is
called an agonist. Conversely, a drug that decreases the availability or action
of an NT is called an antagonist.
drug actions include
being a precursor for an NT, resulting in an increase in NT synthesis:
L-dopa (a precursor for dopamine); trypophan
increasing release of NTs from terminal buttons (e.g., many drugs of abuse
initiate and/or increase the release of dopamine)
acting like endogenous NTs and stimulating postsynaptic receptors (e.g., pain
blocking reuptake by presynaptic neurons, allowing NTs to remain in synapse
immobilizing enzymes that break down NTs in synapse, thus increasing the number
of NTs in the synapse available for action
drug actions include
decreasing the production of an NT by blocking the enzyme required for its
synthesis (e.g., acting on precursors)
blocking storage of NTs in vesicles (e.g., reserpine)
preventing release of NTs (from terminal but-tons (e.g., hyperpolarization)
binding postsynaptic receptors without stimulating them, hindering NT activity
some extent, alcohol on GABA receptors)
stimulating receptors on presynaptic neurons, called autoreceptors, which tell
neurons not to release NTs (possibly the way SSRI work on reducing panic
Cytochrome P450 Enzyme System
of cytochrome P450 liver enzymes is necessary because:
They metabolize most of the drugs we use (by oxidative, reductive or hydrolytic
modification to a more water-soluble form-- for renal excretion).
varying level of their activity in individuals (as a result of different
genetic differences) determines the speed of metabolism of a drug. That in turn
influences the plasma level, efficacy and the side effects.
There is great genetic variation for almost all cytochrome P450 enzymes; both
between individuals within a group (e.g., caucasians) and between groups of
different genetic and ethnic lineages.
example, 2C19 poor metabolizer status is very common in people of Asian
descent. (15% up to nearly 100%) as compared to Caucasians (3-6%). Also, some
people (about 1% of the general population) have 'ultra-fast' 2D6 metabolizers.
There are various endogenous factors (e.g., hormones) and exogenous factors
(e.g. other drugs and foods) that alter the level of CYP450 enzyme activity.
Drugs and foreign biological molecules with similar structures are likely to
have similar properties; so if one member of a group is known to cause problems
others may too.
substances induce P450 enzymes. These are called inducers. This speeds up
this case, more of the drug is eliminated from the body and the pharmaceutical
action of these specific drugs DECREASE.
substances inhibit P450 enzymes. These are called inhibitors. This slows down
metabolism. In this case, less of the drug is eliminate from the body and the
pharmaceutical action of these specific drugs INCREASE.
are more than one thousand P450 enzymes. All P450 enzymes are similar in
structure and mechanism of action. 3A4 is the most abundant in the human liver
and is known to metabolize the majority of drugs whose biotransformation is
large family of enzymes are classified with numbers and letters as follows: the
first number is the CYP P450 family (e.g., 3); the next letter indicates the
sub-type (e.g., A); and the third number indicates the gene product (e.g. 4). A
gene product is defined as the biochemical material, either RNA or protein,
resulting from the expression of a gene)
P450 enzymes that are particularly important for psychotropic drugs are CYP450-1A2, 2D6, 2C9,
2C-19, 3A4 and to a lesser extent 2A6.
important because this enzyme is inhibited by fluvoxamine (Luvox). When Luvox
is given with other drugs that depend on 1A2 for metabolization (such as
theophyllin (Theodur) or clozapine), the level of the other drugs may get
dangerously high (in both cases, this could be life threatening). Some
antibiotics such as Cipro and grapefruit juice also inhibit 1A2.
alergy drug Seldane (terfenadine) was removed from the market in 1998 because
drugs such as ERYTHROMYCIN
3A4, which metabolizes Seldance. In this case, high levels of terfenadine in
your system can lead to death.
all patients treated with even low doses of fluvoxamine (only 50 mg/day) will
reach population minimums for CYP1A2 activity (ie become 'PMs', poor
is also an extremely potent inhibitor of 2C19 and also significant inhibitor of
2C9 and 3A4 (but not of 2D6).
use of fluvoxamine is thus fraught with risks because this potent cytochrome
P450 blockade involves many other commonly used drugs. There are few clinical
situations in which it represents a logical first or second choice treatment in
primary care. When treating the SMI, interactions with neuroleptics, especially
olanzapine and clozapine may cause serious problems.
P450 1A2 metabolises several groups of compounds:
number of important drugs,
some compounds called pro carcinogens (e.g., arylamines in cigarette smoke),
endogenous hormones such as 17beta-estradiol.
fluvoxamine itself (to inactive metabolites, and also via CYP2D6)
caffeine, tacrine, imipramine, haloperidol, pentazocine, phenacetin O-deethylation,
propranolol, flecainide and estradiol and other drugs structurally related to
instance:-- probably all the tertiary amine tricyclic antidepressants***
(clomipramine, amitriptyline, doxepin, dothiepin, but not secondary amines
nortriptyline or desipramine) and also many neuroleptics like clozapine,
tertiary amine tricyclics are those with two methyl groups on the terminal
nitrogen of the side chain. The primary step in metabolism is demethylation to
secondary amines; e.g., amitriptyline is demethylated to nortriptyline
[nicotine may induce the activity of:- CYP1A2, CYP2B1/2B2 and CYP2E1]
aromatic hydrocarbons in tobacco smoke
inducible by the environmental contaminants dioxin and benzo[a]pyrene
levels are markedly elevated by even small doses of fluvoxamine; the most
serious caffeine-related CNS effects include seizures and delirium. A dose of
only 20 mg of fluvoxamine significantly inhibits caffeine (CYP1A2) metabolism.
inhibits 1A2 and that reduces metabolism of caffeine. So exogenous estrogen
given to post menopausal women may inhibit caffeine metabolism (but only by
metabolism of 1A2 because of cigarette smoking may have clinical consequence
for some of these drugs.
and tioconazole:- mexiletine, lidocaine, and (weaker) tocainide
anti-psychotics especially clozapine
(furafylline and theophylline)
a class of phytochemicals consumed in the human diet (found at high
concentrations in 'Tofu") and psoralens
range of flavonoids tested all proved potent inhibitors of CYP1A2
metabolizes, in part or in whole, the
tricyclic drugs which include antihistamines, neuroleptics and tricyclic
antidepressants, and various other drugs. CYP2D6 is potently inhibited by
fluoxetine (Prozac); and paroxetine (Paxil), which may cause significant and
even dangerous, interactions. For example, if Prozac is given together with a
TCA, the levels of TCA can increase into toxic levels.
2D6 plays a significant part in inactivating the following drugs (along with,
in varying proportions, 1A2, 2C9, 3A4)
(and partly 2C19)
of the tricyclic antidepressants
dextropropoxyphene, codeine, (R)-methadone
neuroleptics, including risperidone and sertindole
8% of the Caucasian population are genetically ‘deficient’ in 2D6 which renders
them poor metabolisers and liable to develop considerably elevated blood levels
with all drugs that are dependent on 2D6 for their elimination.
the tricyclic antidepressants nortriptyline and desipramine 2D6 is the main
metabolic pathway. The 8% of Caucasians who are ‘deficient’ in 2D6 and will
have high blood levels (they are referred to as ‘poor metabolisers’ -PMs). Some
people are very rapid ‘extensive’ metabolisers (EMs).
is particularly problematic being a potent 2D6 inhibitor and also a inhibitor
of 3A4 and 2C19. These effects can persist for many weeks after cessation
because of its long elimination half life.
has a small effect that is not usually significant; high doses may raise levels
of co-administered TCAs by around 30%.
inhibitors are likely to cause serious or dangerous interactions in some
circumstances, especially because some of these drugs have a narrow therapeutic
selective serotonin reuptake inhibitor antidepressants, and the other new
antidepressants to date, only fluoxetine and paroxetine are potent inhibitors
of CYP450 2D6.
2D6 INHIBITORS (summary)
is a potent inhibitor of CYP2C9 and extremely for 2C19 and 1A2).
may also cause significant interactions.
(-diazine, methizole, methoxazole)
K(i), 0.01 microM = high affinity
NSAIDs:--diclofenac and ibuprofen other 'profens, mefenamic acid, naproxen,
piroxicam, tenoxicam etc.
intoxication has occurred with fluvoxamine (concentration of phenytoin
increased from 16.6 to 49.1 mcg/m). This suggests significant inhibition of
both CYP2C9 and 2C19 by fluvoxamine.
at the higher dose of 40 mg per day has a significant effect on Phenytoin
levels. The risk of a SSRI-phenytoin interaction is highest with fluoxetine and
norfluoxetine, and less likely with sertraline and paroxetine (which do have
weak 2C9 inhibitor activity).
is likely to convert most patients to poor metaboliser status at usual doses of
100 mg per day for 2C9 (and 1A2). Theory indicates other selective serotonin
reuptake inhibitors are unlikely to have much effect on 2C9.
the case for most cytochrome P450 enzyme inhibition scenarios involving
selective serotonin reuptake inhibitors citalopram (Celexa) and sertraline
(Zoloft) are the safest bet. The other three selective serotonin reuptake
inhibitors, fluoxetine, paroxetine and fluvoxamine all have potentially
problematic and serious cytochrome P450 interactions. They are therefore best
avoided as much as possible by those not fully conversant with the latest data
(drug that is used to treat Arrhythmia)
(extremely potent even at sub-therapuetic doses)
K(i), 0.05 microM; sulconazole K(i), 0.008 microM; tioconazole K(i), 0.04
microM) = high affinity
(N-demethylation to N-desmethylcitalopram- partly by CYP2C19 and partly by
(plays a major role in N-demethylation)
and lansoprazole (most proton pump inhibitors are predominantly inactivated by
polymorphic CYP2C19 appears to be a major enzyme involved in the
N-demethylation of sertraline, extensive vs poor metabolisers had marked
differences in sertraline levels.
is an important enzyme in the elimination of moclobemide and it is inhibited by
Omeprazole in extensive metabolisers, but not in poor metabolisers.
newer antidepressants that are clinically significant inhibitors of CYP450
(mostly its metabolite, nor-fluoxetine)
(much more potent for 1A2 and 2C19 and 2C9)
(other than antidepressants) know to inhibit 3A4 to a clinically significant
antibiotics (especially clarithromycin and erythromycin and, most potent,
K(i), 0.02 microM; miconazole K(i), 0.03 microM; tioconazole K(i), 0.02 microM)
= high affinity
in:-grapefruit juice and seville orange juice (a newly identified furocoumarin,
bergapten, was detected only in Seville orange juice)
in umbelliferous plants such as carrot, parsley, celery, dill (similar potency
compounds in red wine, including trans-resveratrol [sold as a 'nutraceutical'
product]. Red wine concentrate has been shown to inhibit 3A4.
in 'Milk thistle' [the extract is a commonly used herbal remedy]
is the main enzyme inactivating the following common drugs:
of the benzodiazepines (-azepams) including diazepam, flunitrazepam, alprazolam
midazolam, triazolam) and zopiclone and buspirone (but not oxazepam, temazepam
of the old antihistamines, tricyclic antidepressants and both old and new
neuroleptics*. eg Quetiapine, azelastine
(CYP3A, CYP1A2 and CYP2D6 contribute about equally)
most of these drugs, including amitriptyline, chlorpromazine, clozapine and
olanzapine are metabolised by multiple CYP enzymes including P450 1A2 and 2C9
-inhibitor of CYP3A4, had minimal effects on clozapine metabolism. When nefazodone
treatment follows fluoxetine all sorts of interesting things may happen which
might result in significant clinical problems, and should be done carefully).
disulfides [di-n-propyl disulfide, contained in onion oil- the most potent]
disulfide, present in garlic oil
(Alpha 2 agonist- sedative)
(urinary cotinine, one of the main metabolites of nicotine, has been widely
used as a biomarker for assessment of direct or passive exposure to cigarette
(marker, caffeine metabolite)