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GENERAL

PHARMACOLOGY
-2

By G.RAGHAVENDER REDDY
(MBBS)stu, ZSMU
grreddy836@gmail.com

CONTENTS

Drug metabolism

Xenobiotic metabolism

Enzyme inhibitor

Pharmacognosy

Pharmacophore
Galenic formulation

Pharmacopoeia

Pharmaceutical formulation

Dosage form

Route of administration

Injection ( medicine )

Drug injection

Catheter

Medical inhalants

Drug metabolism
Drug metabolism is the metabolism of drugs, their biochemical modification or
degradation, usually through specialized enzymatic systems. This is a form of
xenobiotic metabolism. Drug metabolism often converts lipophilic chemical
compounds into more readily excreted polar products. Its rate is an important
determinant of the duration and intensity of the pharmacological action of drugs.

Drug metabolism can result in toxication or detoxication - the activation or


deactivation of the chemical. While both occur, the major metabolites of most
drugs are detoxication products.

Drugs are almost all xenobiotics. Other commonly used organic chemicals are
also xenobiotics, and are metabolized by the same enzymes as drugs. This
provides the opportunity for drug-drug and drug-chemical interactions or
reactions.
Contents

* 1 Phase I vs. Phase II


* 2 Sites
* 3 Major enzymes and pathways
o 3.1 Phase I
+ 3.1.1 Oxidation
+ 3.1.2 Reduction
+ 3.1.3 Hydrolysis
o 3.2 Phase II
+ 3.2.1 Methylation
+ 3.2.2 Sulphation
+ 3.2.3 Acetylation
+ 3.2.4 Glucuronidation
* 4 Factors that affect Drug Metabolism
* 5 See also
* 6 References
* 7 External links

Phase I vs. Phase II

Phase I and Phase II reactions are biotransformations of chemicals that occur


during drug metabolism.

Phase I reactions usually precede Phase II, though not necessarily. During these
reactions, polar bodies are either introduced or unmasked, which results in
(more) polar metabolites of the original chemicals. In the case of pharmaceutical
drugs, Phase I reactions can lead either to activation or inactivation of the drug.

Phase I reactions (also termed nonsynthetic reactions) may occur by oxidation,


reduction, hydrolysis, cyclization, and decyclization reactions. Oxidation involves
the enzymatic addition of oxygen or removal of hydrogen, carried out by mixed
function oxidases, often in the liver. These oxidative reactions typically involve a
cytochrome P450 monooxygenase (often abbreviated CYP), NADPH and oxygen.
The classes of pharmaceutical drugs that utilize this method for their metabolism
include phenothiazines, paracetamol, and steroids. If the metabolites of phase I
reactions are sufficiently polar, they may be readily excreted at this point.
However, many phase I products are not eliminated rapidly and undergo a
subsequent reaction in which an endogenous substrate combines with the newly
incorporated functional group to form a highly polar conjugate.

A common Phase I oxidation involves conversion of a C-H bond to a C-OH. This


reaction sometimes converts a pharmacologically inactive compound (a prodrug)
to a pharmacologically active one. By the same token, Phase I can turn a nontoxic
molecule into a poisonous one (toxification). A famous example is acetonitrile,
CH3CN. Simple hydrolysis in the stomach transforms acetonitrile into acetate and
ammonia, which are comparatively innocuous. But Phase I metabolism converts
acetonitrile to HOCH2CN, which rapidly dissociates into formaldehyde and
hydrogen cyanide, both of which are toxic.

Phase I metabolism of drug candidates can be simulated in the laboratory using


non-enzyme catalysts.[1] This example of a biomimetic reaction tends to give a
mixture of products that often contains the Phase I metabolites, and Alpha
Chimica's approach to preparing prospective drug candidates makes use of this
in vitro chemistry.

Phase II reactions — usually known as conjugation reactions (e.g., with


glucuronic acid, sulfonates (commonly known as sulfation) , glutathione or amino
acids) — are usually detoxication in nature, and involve the interactions of the
polar functional groups of phase I metabolites. Sites on drugs where conjugation
reactions occur include carboxyl (-COOH), hydroxyl (-OH), amino (NH2), and
sulfhydryl (-SH) groups. Products of conjugation reactions have increased
molecular weight and are usually inactive unlike Phase I reactions which often
produce active metabolites.
Sites

Quantitatively, the smooth endoplasmic reticulum of the liver cell is the principal
organ of drug metabolism, although every biological tissue has some ability to
metabolize drugs. Factors responsible for the liver's contribution to drug
metabolism include that it is a large organ, that it is the first organ perfused by
chemicals absorbed in the gut, and that there are very high concentrations of
most drug-metabolizing enzyme systems relative to other organs. If a drug is
taken into the GI tract, where it enters hepatic circulation through the portal vein,
it becomes well-metabolized and is said to show the first pass effect.

Other sites of drug metabolism include epithelial cells of the gastrointestinal


tract, lungs, kidneys, and the skin. These sites are usually responsible for
localized toxicity reactions.

Major enzymes and pathways

Several major enzymes and pathways are involved in drug metabolism, and can
be divided into Phase I and Phase II reactions:
Phase I

Oxidation

* Cytochrome P450 monooxygenase system


* Flavin-containing monooxygenase system
* Alcohol dehydrogenase and aldehyde dehydrogenase
* Monoamine oxidase
* Co-oxidation by peroxidases

Reduction

* NADPH-cytochrome P450 reductase


* Reduced (ferrous) cytochrome P450

It should be noted that during reduction reactions, a chemical can enter futile
cycling, in which it gains a free-radical electron, then promptly loses it to oxygen
(to form a superoxide anion).

Hydrolysis

* Esterases and amidases


* Epoxide hydrolase

Phase II

Methylation

* methyltransferase

Sulphation

* Glutathione S-transferases
* Sulfotransferases

Acetylation

* N-acetyltransferases
* Amino acid N-acyl transferases

Glucuronidation

* UDP-glucuronosyltransferases
o Mercapturic acid biosynthesis

Factors that affect Drug Metabolism


The duration and intensity of pharmacological action of most lipophilic drugs are
determined by the rate they are metabolized to inactive products. The
Cytochrome P450 monooxygenase system is the most important pathway in this
regard. In general, anything that increases the rate of metabolism (e.g., enzyme
induction) of a pharmacologically active metabolite will decrease the duration and
intensity of the drug action. The opposite is also true (e.g., enzyme inhibition).

Various physiological and pathological factors can also affect drug metabolism.
Physiological factors that can influence drug metabolism include age, individual
variation (e.g., pharmacogenetics), enterohepatic circulation, nutrition, intestinal
flora, or sex differences.

In general, drugs are metabolized more slowly in fetal, neonatal and elderly
humans and animals than in adults.

Genetic variation (polymorphism) accounts for some of the variability in the effect
of drugs. With N-acetyltransferases (involved in Phase II reactions), individual
variation creates a group of people who acetylate slowly (slow acetylators) and
those who acetylate quickly, split roughly 50:50 in the population of Canada. This
variation may have dramatic consequences, as the slow acetylators are more
prone to dose-dependent toxicity.

Cytochrome P450 monooxygenase system enzymes can also vary across


individuals, with deficiencies occurring in 1 - 30% of people, depending on their
ethnic background.

Pathological factors can also influence drug metabolism, including liver, kidney,
or heart diseases.

In silico modelling and simulation methods allow drug metabolism to be


predicted in virtual patient populations prior to performing clinical studies in
human subjects.This can be used to identify individuals most at risk from
adverse reaction.

See also

Xenobiotic metabolism
Xenobiotic metabolism is the set of metabolic pathways that modify the chemical
structure of xenobiotics, which are compounds foreign to an organism's normal
biochemistry, such as drugs and poisons. These pathways are a form of
biotransformation present in all major groups of organisms, and are considered
to be of ancient origin. These reactions often act to detoxify poisonous
compounds; however, in some cases, the intermediates in xenobiotic metabolism
can themselves be the cause of toxic effects.

Xenobiotic metabolism is divided into three phases. In phase I, enzymes such as


cytochrome P450 oxidases introduce reactive or polar groups into xenobiotics.
These modified compounds are then conjugated to polar compounds in phase II
reactions. These reactions are catalysed by transferase enzymes such as
glutathione S-transferases. Finally, in phase III, the conjugated xenobiotics may
be further processed, before being recognised by efflux transporters and pumped
out of cells.

The reactions in these pathways are of particular interest in medicine as part of


drug metabolism and as a factor contributing to multidrug resistance in
infectious diseases and cancer chemotherapy. The actions of some drugs as
substrates or inhibitors of enzymes involved in xenobiotic metabolism are a
common reason for hazardous drug interactions. These pathways are also
important in environmental science, with the xenobiotic metabolism of
microorganisms determining whether a pollutant will be broken down during
bioremediation, or persist in the environment. The enzymes of xenobiotic
metabolism, particularly the glutathione S-transferases are also important in
agriculture, since they may produce resistance to pesticides and herbicides.
Contents

* 1 Permeability barriers and detoxification


* 2 Phases of detoxification
o 2.1 Phase I - modification
o 2.2 Phase II - conjugation
o 2.3 Phase III - further modification and excretion
* 3 Endogenous toxins
* 4 History
* 5 See also
* 6 References
* 7 Further reading
* 8 External links

Permeability barriers and detoxification

That the exact compounds an organism is exposed to will be largely


unpredictable, and may differ widely over time, is a major characteristic of
xenobiotic toxic stress. The major challenge faced by xenobiotic detoxification
systems is that they must be able to remove the almost-limitless number of
xenobiotic compounds from the complex mixture of chemicals involved in normal
metabolism. The solution that has evolved to address this problem is an elegant
combination of physical barriers and low-specificity enzymatic systems.

All organisms use cell membranes as hydrophobic permeability barriers to


control access to their internal environment. Polar compounds cannot diffuse
across these cell membranes, and the uptake of useful molecules is mediated
through transport proteins that specifically select substrates from the
extracellular mixture. This selective uptake means that most hydrophilic
molecules cannot enter cells, since they are not recognised by any specific
transporters. In contrast, the diffusion of hydrophobic compounds across these
barriers cannot be controlled, and organisms, therefore, cannot exclude lipid-
soluble xenobiotics using membrane barriers.

However, the existence of a permeability barrier means that organisms were able
to evolve detoxification systems that exploit the hydrophobicity common to
membrane-permeable xenobiotics. These systems therefore solve the specificity
problem by possessing such broad substrate specificities that they metabolise
almost any non-polar compound. Useful metabolites are excluded since they are
polar, and in general contain one or more charged groups.

The detoxification of the reactive by-products of normal metabolism cannot be


achieved by the systems outlined above, because these species are derived from
normal cellular constituents and usually share their polar characteristics.
However, since these compounds are few in number, specific enzymes can
recognize and remove them. Examples of these specific detoxification systems
are the glyoxalase system, which removes the reactive aldehyde methylglyoxal,
and the various antioxidant systems that eliminate reactive oxygen species.

Phases of detoxification
Phases I and II of the metabolism of a lipophilic xenobiotic.

The metabolism of xenobiotics is often divided into three phases: modification,


conjugation, and excretion. These reactions act in concert to detoxify xenobiotics
and remove them from cells.

Phase I - modification

In phase I, a variety of enzymes acts to introduce reactive and polar groups into
their substrates. One of the most common modifications is hydroxylation
catalysed by the cytochrome P-450-dependent mixed-function oxidase system.
These enzyme complexes act to incorporate an atom of oxygen into nonactivated
hydrocarbons, which can result in either the introduction of hydroxyl groups or
N-, O- and S-dealkylation of substrates. The reaction mechanism of the P-450
oxidases proceeds through the reduction of cytochrome-bound oxygen and the
generation of a highly-reactive oxyferryl species, according to the following
scheme:
\mbox{NADPH} + \mbox{H}^+ + \mbox{RH} \rightarrow \mbox{NADP}^+ +
\mbox{H}_2\mbox{O} +\mbox{ROH} \,

Phase II - conjugation

In subsequent phase II reactions, these activated xenobiotic metabolites are


conjugated with charged species such as glutathione (GSH), sulfate, glycine, or
glucuronic acid. These reactions are catalysed by a large group of broad-
specificity transferases, which in combination can metabolise almost any
hydrophobic compound that contains nucleophilic or electrophilic groups. One of
the most important of these groups are the glutathione S-transferases (GSTs).
The addition of large anionic groups (such as GSH) detoxifies reactive
electrophiles and produces more polar metabolites that cannot diffuse across
membranes, and may, therefore, be actively transported.

Phase III - further modification and excretion

After phase II reactions, the xenobiotic conjugates may be further


metabolised. A common example is the processing of glutathione
conjugates to acetylcysteine (mercapturic acid) conjugates.[7] Here,
the γ-glutamate and glycine residues in the glutathione molecule are removed
by Gamma-glutamyl transpeptidase and dipeptidases. In the final step, the
cystine residue in the conjugate is acetylated.

Conjugates and their metabolites can be excreted from cells in phase III of their
metabolism, with the anionic groups acting as affinity tags for a variety of
membrane transporters of the multidrug resistance protein (MRP) family. These
proteins are members of the family of ATP-binding cassette transporters and can
catalyse the ATP-dependent transport of a huge variety of hydrophobic anions,
and thus act to remove phase II products to the extracellular medium, where they
may be further metabolised or excreted.

Endogenous toxins

The detoxification of endogenous reactive metabolites such as peroxides and


reactive aldehydes often cannot be achieved by the system described above. This
is the result of these species' being derived from normal cellular constituents and
usually sharing their polar characteristics. However, since these compounds are
few in number, it is possible for enzymatic systems to utilize specific molecular
recognition to recognize and remove them. The similarity of these molecules to
useful metabolites therefore means that different detoxification enzymes are
usually required for the metabolism of each group of endogenous toxins.
Examples of these specific detoxification systems are the glyoxalase system,
which acts to dispose of the reactive aldehyde methylglyoxal, and the various
antioxidant systems that remove reactive oxygen species.
History

Studies on how people transform the substances that they ingest began in the
mid-nineteenth century, with chemists discovering that organic chemicals such
as benzaldehyde could be oxidized and conjugated to amino acids in the human
body. During the remainder of the nineteenth century, several other basic
detoxification reactions were discovered, such as methylation, acetylation, and
sulfonation.

In the early twentieth century, work moved on to the investigation of the enzymes
and pathways that were responsible for the production of these metabolites. This
field became defined as a separate area of study with the publication by Richard
Williams of the book Detoxication mechanisms in 1947. This modern biochemical
research resulted in the identification of glutathione S-transferases in
1961,followed by the discovery of cytochrome P450s in 1962, and the realization
of their central role in xenobiotic metabolism in 1963.

Enzyme inhibitor
Enzyme inhibitors are molecules that bind to enzymes and decrease their activity.
Since blocking an enzyme's activity can kill a pathogen or correct a metabolic
imbalance, many drugs are enzyme inhibitors. They are also used as herbicides
and pesticides. Not all molecules that bind to enzymes are inhibitors; enzyme
activators bind to enzymes and increase their enzymatic activity.

The binding of an inhibitor can stop a substrate from entering the enzyme's active
site and/or hinder the enzyme from catalysing its reaction. Inhibitor binding is
either reversible or irreversible. Irreversible inhibitors usually react with the
enzyme and change it chemically. These inhibitors modify key amino acid
residues needed for enzymatic activity. In contrast, reversible inhibitors bind non-
covalently and different types of inhibition are produced depending on whether
these inhibitors bind the enzyme, the enzyme-substrate complex, or both.

Many drug molecules are enzyme inhibitors, so their discovery and improvement
is an active area of research in biochemistry and pharmacology. A medicinal
enzyme inhibitor is often judged by its specificity (its lack of binding to other
proteins) and its potency (its dissociation constant, which indicates the
concentration needed to inhibit the enzyme). A high specificity and potency
ensure that a drug will have few side effects and thus low toxicity.

Enzyme inhibitors also occur naturally and are involved in the regulation of
metabolism. For example, enzymes in a metabolic pathway can be inhibited by
downstream products. This type of negative feedback slows flux through a
pathway when the products begin to build up and is an important way to maintain
homeostasis in a cell. Other cellular enzyme inhibitors are proteins that
specifically bind to and inhibit an enzyme target. This can help control enzymes
that may be damaging to a cell, such as proteases or nucleases; a well-
characterised example is the ribonuclease inhibitor, which binds to ribonucleases
in one of the tightest known protein–protein interactions. Natural enzyme
inhibitors can also be poisons and are used as defenses against predators or as
ways of killing prey.
Contents

* 1 Reversible inhibitors
o 1.1 Types of reversible inhibitor
o 1.2 Quantitative description of reversible inhibition
o 1.3 Measuring the dissociation constants of a reversible inhibitor
o 1.4 Special cases
o 1.5 Examples of reversible inhibitors
* 2 Irreversible inhibitors
o 2.1 Types of irreversible inhibition
o 2.2 Analysis of irreversible inhibition
o 2.3 Special cases
o 2.4 Examples of irreversible inhibitors
* 3 Discovery and design of inhibitors
* 4 Uses of inhibitors
o 4.1 Chemotherapy
o 4.2 Metabolic control
o 4.3 Acetylcholinesterase inhibitors
o 4.4 Natural poisons
* 5 See also
* 6 References
* 7 External links

Reversible inhibitors

Types of reversible inhibitor

Reversible inhibitors bind to enzymes with non-covalent interactions such as


hydrogen bonds, hydrophobic interactions and ionic bonds. Multiple weak bonds
between the inhibitor and the active site combine to produce strong and specific
binding. In contrast to substrates and irreversible inhibitors, reversible inhibitors
generally do not undergo chemical reactions when bound to the enzyme and can
be easily removed by dilution or dialysis.
Competitive inhibition: substrate (S) and inhibitor (I) compete for the active site.
There are four kinds of reversible enzyme inhibitors. They are classified
according to the effect of varying the concentration of the enzyme's substrate on
the inhibitor.

* In competitive inhibition, the substrate and inhibitor cannot bind to the


enzyme at the same time, as shown in the figure on the left. This usually results
from the inhibitor having an affinity for the active site of an enzyme where the
substrate also binds; the substrate and inhibitor compete for access to the
enzyme's active site. This type of inhibition can be overcome by sufficiently high
concentrations of substrate, i.e., by out-competing the inhibitor. Competitive
inhibitors are often similar in structure to the real substrate (see examples
below).

* In uncompetitive inhibition, the inhibitor binds only to the substrate-enzyme


complex, it should not be confused with non-competitive inhibitors. Both
maximum velocity (Vmax) and binding efficiency (Km) decrease.

* In mixed inhibition, the inhibitor can bind to the enzyme at the same time as
the enzyme's substrate. However, the binding of the inhibitor affects the binding
of the substrate, and vice versa. This type of inhibition can be reduced, but not
overcome by increasing concentrations of substrate. Although it is possible for
mixed-type inhibitors to bind in the active site, this type of inhibition generally
results from an allosteric effect where the inhibitor binds to a different site on an
enzyme. Inhibitor binding to this allosteric site changes the conformation (i.e.,
tertiary structure or three-dimensional shape) of the enzyme so that the affinity of
the substrate for the active site is reduced.

* Non-competitive inhibition is a form of mixed inhibition where the binding of


the inhibitor to the enzyme reduces its activity but does not affect the binding of
substrate. As a result, the extent of inhibition depends only on the concentration
of the inhibitor.

Quantitative description of reversible inhibition

Reversible inhibition can be described quantitatively in terms of the inhibitor's


binding to the enzyme and to the enzyme–substrate complex, and its effects on
the kinetic constants of the enzyme. In the classic Michaelis–Menten scheme
below, an enzyme (E) binds to its substrate (S) to form the enzyme–substrate
complex ES. Upon catalysis, this complex breaks down to release product P and
free enzyme. The inhibitor (I) can bind to either E or ES with the dissociation
constants Ki or Ki', respectively.

* Competitive inhibitors can bind to E, but not to ES. Competitive inhibition


increases Km (i.e., the inhibitor interferes with substrate binding), but does not
affect Vmax (the inhibitor does not hamper catalysis in ES because it cannot bind
to ES).
* Non-competitive inhibitors have identical affinities for E and ES (Ki = Ki').
Non-competitive inhibition does not change Km (i.e., it does not affect substrate
binding) but decreases Vmax (i.e., inhibitor binding hampers catalysis).

* Mixed-type inhibitors bind to both E and ES, but their affinities for these two
forms of the enzyme are different (Ki ≠ Ki'). Thus, mixed-type inhibitors interfere
with substrate binding (increase Km) and hamper catalysis in the ES complex
(decrease Vmax).

Kinetic scheme for reversible enzyme inhibitors

When an enzyme has multiple substrates, inhibitors can show different types of
inhibition depending on which substrate is considered. This results from the
active site containing two different binding sites within the active site, one for
each substrate. For example, an inhibitor might compete with substrate A for the
first binding site, but be a non-competitive inhibitor with respect to substrate B in
the second binding site.

Measuring the dissociation constants of a reversible inhibitor


Lineweaver–Burk plots of different types of reversible enzyme inhibitors. The
arrow shows the effect of increasing concentrations of inhibitor.

As noted above, an enzyme inhibitor is characterized by its two dissociation


constants, Ki and Ki', to the enzyme and to the enzyme-substrate complex,
respectively. The enzyme-inhibitor constant Ki can be measured directly by
various methods; one extremely accurate method is isothermal titration
calorimetry, in which the inhibitor is titrated into a solution of enzyme and the
heat released or absorbed is measured.However, the other dissociation constant
Ki' is difficult to measure directly, since the enzyme-substrate complex is short-
lived and undergoing a chemical reaction to form the product. Hence, Ki' is
usually measured indirectly, by observing the enzyme activity under various
substrate and inhibitor concentrations, and fitting the data[5] to a modified
Michaelis–Menten equation

V = \frac{V_{max}[S]}{\alpha K_{m} + \alpha^{\prime}[S]} =


\frac{(1/\alpha^{\prime})V_{max}[S]}{(\alpha/\alpha^{\prime}) K_{m} + [S]}

where the modifying factors α and α' are defined by the inhibitor
concentration and its two dissociation constants

\alpha = 1 + \frac{[I]}{K_{i}}
\alpha^{\prime} = 1 + \frac{[I]}{K_{i}^{\prime}}.

Thus, in the presence of the inhibitor, the enzyme's effective Km


and Vmax become (α/α')Km and (1/α')Vmax, respectively. However,
the modified Michaelis-Menten equation assumes that binding of
the inhibitor to the enzyme has reached equilibrium, which may be a
very slow process for inhibitors with sub-nanomolar dissociation constants. In
these cases, it is usually more practical to treat the tight-binding inhibitor as an
irreversible inhibitor (see below); however, it can still be possible to estimate Ki'
kinetically if Ki is measured independently.

The effects of different types of reversible enzyme inhibitors on enzymatic


activity can be visualized using graphical representations of the Michaelis–
Menten equation, such as Lineweaver–Burk and Eadie-Hofstee plots. For
example, in the Lineweaver–Burk plots at the right, the competitive inhibition
lines intersect on the y-axis, illustrating that such inhibitors do not affect Vmax.
Similarly, the non-competitive inhibition lines intersect on the x-axis, showing
these inhibitors do not affect Km. However, it can be difficult to estimate Ki and
Ki' accurately from such plots,[6] so it is advisable to estimate these constants
using more reliable nonlinear regression methods, as described above.

Special cases

The mechanism of partially competitive inhibition is similar to that of non-


competitive, except that the EIS complex has catalytic activity, which may be
lower or even higher (partially competitive activation) than that of the enzyme–
substrate (ES) complex. This inhibition typically displays a lower Vmax, but an
unaffected Km value.

* Uncompetitive inhibition occurs when the inhibitor binds only to the enzyme–
substrate complex, not to the free enzyme; the EIS complex is catalytically
inactive. This mode of inhibition is rare and causes a decrease in both Vmax and
the Km value.

* Substrate and product inhibition is where either the substrate or product of


an enzyme reaction inhibit the enzyme's activity. This inhibition may follow the
competitive, uncompetitive or mixed patterns. In substrate inhibition there is a
progressive decrease in activity at high substrate concentrations. This may
indicate the existence of two substrate-binding sites in the enzyme. At low
substrate, the high-affinity site is occupied and normal kinetics are followed.
However, at higher concentrations, the second inhibitory site becomes occupied,
inhibiting the enzyme. Product inhibition is often a regulatory feature in
metabolism and can be a form of negative feedback.

* Slow-tight inhibition occurs when the initial enzyme–inhibitor complex EI


undergoes isomerisation to a second more tightly held complex, EI*, but the
overall inhibition process is reversible. This manifests itself as slowly increasing
enzyme inhibition. Under these conditions, traditional Michaelis–Menten kinetics
give a false value for Ki, which is time–dependent. The true value of Ki can be
obtained through more complex analysis of the on (kon) and off (koff) rate
constants for inhibitor association. See irreversible inhibition below for more
information.

Examples of reversible inhibitors


Peptide-based protease inhibitor ritonavir

As enzymes have evolved to bind their substrates tightly, and most reversible
inhibitors bind in the active site of enzymes, it is unsurprising that some of these
inhibitors are strikingly similar in structure to the substrates of their targets. An
example of these substrate mimics are the protease inhibitors, a very successful
class of antiretroviral drugs used to treat HIV. The structure of ritonavir, a
protease inhibitor based on a peptide and containing three peptide bonds, is
shown on the right. As this drug resembles the protein that is the substrate of the
HIV protease, it competes with this substrate in the enzyme's active site.

Enzyme inhibitors are often designed to mimic the transition state or intermediate
of an enzyme-catalysed reaction. This ensures that the inhibitor exploits the
transition state stabilising effect of the enzyme, resulting in a better binding
affinity (lower Ki) than substrate-based designs. An example of such a transition
state inhibitor is the antiviral drug oseltamivir; this drug mimics the planar nature
of the ring oxonium ion in the reaction of the viral enzyme neuraminidase.
Nonpeptidic protease inhibitor tipranavir

However, not all inhibitors are based on the structures of substrates. For
example, the structure of another HIV protease inhibitor tipranavir is shown on
the left. This molecule is not based on a peptide and has no obvious structural
similarity to a protein substrate. These non-peptide inhibitors can be more stable
than inhibitors containing peptide bonds, because they will not be substrates for
peptidases and are less likely to be degraded.

In drug design it is important to consider the concentrations of substrates to


which the target enzymes are exposed. For example, some protein kinase
inhibitors have chemical structures that are similar to adenosine triphosphate,
one of the substrates of these enzymes. However, drugs that are simple
competitive inhibitors will have to compete with the high concentrations of ATP
in the cell. Protein kinases can also be inhibited by competition at the binding
sites where the kinases interact with their substrate proteins, and most proteins
are present inside cells at concentrations much lower than the concentration of
ATP. As a consequence, if two protein kinase inhibitors both bind in the active
site with similar affinity, but only one has to compete with ATP, then the
competitive inhibitor at the protein-binding site will inhibit the enzyme more
effectively.

Irreversible inhibitors
Types of irreversible inhibition
Reaction of the irreversible inhibitor diisopropylfluorophosphate (DFP) with a
serine protease

Irreversible inhibitors usually covalently modify an enzyme, and inhibition cannot


therefore be reversed. Irreversible inhibitors often contain reactive functional
groups such as nitrogen mustards, aldehydes, haloalkanes, alkenes, Michael
acceptors, phenyl sulphonates, or fluorophosphonates. These electrophilic
groups react with amino acid side chains to form covalent adducts. The residues
modified are those with side chains containing nucleophiles such as hydroxyl or
sulfhydryl groups; these include the amino acids serine (as in DFP, right),
cysteine, threonine or tyrosine.

Irreversible inhibition is different from irreversible enzyme inactivation.


Irreversible inhibitors are generally specific for one class of enzyme and do not
inactivate all proteins; they do not function by destroying protein structure but by
specifically altering the active site of their target. For example, extremes of pH or
temperature usually cause denaturation of all protein structure, but this is a non-
specific effect. Similarly, some non-specific chemical treatments destroy protein
structure: for example, heating in concentrated hydrochloric acid will hydrolyse
the peptide bonds holding proteins together, releasing free amino acids

Irreversible inhibitors display time-dependent inhibition and their potency


therefore cannot be characterized by an IC50 value. This is because the amount
of active enzyme at a given concentration of irreversible inhibitor will be different
depending on how long the inhibitor is pre-incubated with the enzyme. Instead,
kobs/[I] values are used,[15] wherekobs is the observed pseudo-first order rate of
inactivation (obtained by plotting the log of % activity vs. time) and [I] is the
concentration of inhibitor. The kobs/[I] parameter is valid as long as the inhibitor
does not saturate binding with the enzyme (in which case kobs = kinact).

[edit] Analysis of irreversible inhibition


Kinetic scheme for irreversible inhibitors

As shown in the figure to the left, irreversible inhibitors form a reversible non-
covalent complex with the enzyme (EI or ESI) and this then reacts to produce the
covalently modified "dead-end complex" EI*. The rate at which EI* is formed is
called the inactivation rate or kinact. Since formation of EI may compete with ES,
binding of irreversible inhibitors can be prevented by competition either with
substrate or with a second, reversible inhibitor. This protection effect is good
evidence of a specific reaction of the irreversible inhibitor with the active site.

The binding and inactivation steps of this reaction are investigated by incubating
the enzyme with inhibitor and assaying the amount of activity remaining over
time. The activity will be decrease in a time-dependent manner, usually following
exponential decay. Fitting these data to a rate equation gives the rate of
inactivation at this concentration of inhibitor. This is done at several different
concentrations of inhibitor. If a reversible EI complex is involved the inactivation
rate will be saturable and fitting this curve will give kinact and Ki.

Another method that is widely used in these analyses is mass spectrometry.


Here, accurate measurement of the mass of the unmodified native enzyme and
the inactivated enzyme gives the increase in mass caused by reaction with the
inhibitor and shows the stoichiometry of the reaction. This is usually done using
a MALDI-TOF mass spectrometer. In a complementary technique, peptide mass
fingerprinting involves digestion of the native and modified protein with a
protease such as trypsin. This will produce a set of peptides that can be analysed
using a mass spectrometer. The peptide that changes in mass after reaction with
the inhibitor will be the one that contains the site of modification.

Special cases
Chemical mechanism for irreversible inhibition of ornithine decarboxylase by
DFMO. Pyridoxal 5'-phosphate (Py) and enzyme (E) are not shown. Adapted from

Not all irreversible inhibitors form covalent adducts with their enzyme targets.
Some reversible inhibitors bind so tightly to their target enzyme that they are
essentially irreversible. These tight-binding inhibitors may show kinetics similar
to covalent irreversible inhibitors. In these cases, some of these inhibitors rapidly
bind to the enzyme in a low-affinity EI complex and this then undergoes a slower
rearrangement to a very tightly bound EI* complex (see figure above). This kinetic
behaviour is called slow-binding This slow rearrangement after binding often
involves a conformational change as the enzyme "clamps down" around the
inhibitor molecule. Examples of slow-binding inhibitors include some important
drugs, such methotrexate, allopurinol,and the activated form of acyclovir.

Examples of irreversible inhibitors


Trypanothione reductase with the lower molecule of an inhibitor bound
irreversibly and the upper one reversibly. Created from PDB 1GXF.

Diisopropylfluorophosphate (DFP) is shown as an example of an irreversible


protease inhibitor in the figure above right. The enzyme hydrolyses the
phosphorus–fluorine bond, but the phosphate residue remains bound to the
serine in the active site, deactivating it. Similarly, DFP also reacts with the active
site of acetylcholine esterase in the synapses of neurons, and consequently is a
potent neurotoxin, with a lethal dose of less than 100 mg.

Suicide inhibition is an unusual type of irreversible inhibition where


the enzyme converts the inhibitor into a reactive form in its active
site. An example is the inhibitor of polyamine biosynthesis, α-
difluoromethylornithine or DFMO, which is an analogue of the amino
acid ornithine, and is used to treat African trypanosomiasis (sleeping sickness).
Ornithine decarboxylase can catalyse the decarboxylation of DFMO instead of
ornithine, as shown above. However, this decarboxylation reaction is followed by
the elimination of a fluorine atom, which converts this catalytic intermediate into
a conjugated imine, a highly electrophilic species. This reactive form of DFMO
then reacts with either a cysteine or lysine residue in the active site to irreversibly
inactivate the enzyme.

Since irreversible inhibition often involves the initial formation of a non-covalent


EI complex, it is sometimes possible for an inhibitor to bind to an enzyme in more
than one way. For example, in the figure showing trypanothione reductase from
the human protozoan parasite Trypanosoma cruzi, two molecules of an inhibitor
called quinacrine mustard are bound in its active site. The top molecule is bound
reversibly, but the lower one is bound covalently as it has reacted with an amino
acid residue through its nitrogen mustard group.

Discovery and design of inhibitors


Robots used for the high-throughput screening of chemical libraries to discover
new enzyme inhibitors

New drugs are the products of a long drug development process, the first step of
which is often the discovery of a new enzyme inhibitor. In the past the only way to
discover these new inhibitors was by trial and error: screening huge libraries of
compounds against a target enzyme and hoping that some useful leads would
emerge. This brute force approach is still successful and has even been extended
by combinatorial chemistry approaches that quickly produce large numbers of
novel compounds and high-throughput screening technology to rapidly screen
these huge chemical libraries for useful inhibitors.

More recently, an alternative approach has been applied: rational drug design
uses the three-dimensional structure of an enzyme's active site to predict which
molecules might be inhibitors. These predictions are then tested and one of these
tested compounds may be a novel inhibitor. This new inhibitor is then used to try
to obtain a structure of the enzyme in an inhibitor/enzyme complex to show how
the molecule is binding to the active site, allowing changes to be made to the
inhibitor to try to optimise binding. This test and improve cycle is then repeated
until a sufficiently potent inhibitor is produced. Computer-based methods of
predicting the affinity of an inhibitor for an enzyme are also being developed,
such as molecular docking and molecular mechanics.

Uses of inhibitors

Enzyme inhibitors are found in nature and are also designed and produced as
part of pharmacology and biochemistry. Natural poisons are often enzyme
inhibitors that have evolved to defend a plant or animal against predators. These
natural toxins include some of the most poisonous compounds known. Artificial
inhibitors are often used as drugs, but can also be insecticides such as
malathion, herbicides such as glyphosate, or disinfectants such as triclosan.
Chemotherapy
The structure of sildenafil (Viagra)
The coenzyme folic acid (left) compared to the anti-cancer drug methotrexate
(right)
The structure of a complex between penicillin G and the Streptomyces
transpeptidase. Generated from PDB 1PWC.

The most common uses for enzyme inhibitors are as drugs to treat disease. Many
of these inhibitors target a human enzyme and aim to correct a pathological
condition. However, not all drugs are enzyme inhibitors. Some, such as anti-
epileptic drugs, alter enzyme activity by causing more or less of the enzyme to be
produced. These effects are called enzyme induction and inhibition and are
alterations in gene expression, which is unrelated to the type of enzyme inhibition
discussed here. Other drugs interact with cellular targets that are not enzymes,
such as ion channels or membrane receptors.

An example of a medicinal enzyme inhibitor is sildenafil (Viagra), a common


treatment for male erectile dysfunction. This compound is a potent inhibitor of
cGMP specific phosphodiesterase type 5, the enzyme that degrades the
signalling molecule cyclic guanosine monophosphate.[30] This signalling
molecule triggers smooth muscle relaxation and allows blood flow into the
corpus cavernosum, which causes an erection. Since the drug decreases the
activity of the enzyme that halts the signal, it makes this signal last for a longer
period of time.

Another example of the structural similarity of some inhibitors to the substrates


of the enzymes they target is seen in the figure comparing the drug methotrexate
to folic acid. Folic acid is a substrate of dihydrofolate reductase, an enzyme
involved in making nucleotides that is potently inhibited by methotrexate.
Methotrexate blocks the action of dihydrofolate reductase and thereby halts the
production of nucleotides. This block of nucleotide biosynthesis is more toxic to
rapidly growing cells than non-dividing cells, since a rapidly-growing cell has to
carry out DNA replication, therefore methotrexate is often used in cancer
chemotherapy.

Drugs also are used to inhibit enzymes needed for the survival of pathogens. For
example, bacteria are surrounded by a thick cell wall made of a net-like polymer
called peptidoglycan. Many antibiotics such as penicillin and vancomycin inhibit
the enzymes that produce and then cross-link the strands of this polymer
together. This causes the cell wall to lose strength and the bacteria to burst. In
the figure, a molecule of penicillin (shown in a ball-and stick form) is shown
bound to its target, the transpeptidase from the bacteria Streptomyces R61 (the
protein is shown as a ribbon-diagram).

Drug design is facilitated when an enzyme that is essential to the pathogen's


survival is absent or very different in humans. In the example above, humans do
not make peptidoglycan, therefore inhibitors of this process are selectively toxic
to bacteria. Selective toxicity is also produced in antibiotics by exploiting
differences in the structure of the ribosomes in bacteria, or how they make fatty
acids.

[edit] Metabolic control

Enzyme inhibitors are also important in metabolic control. Many metabolic


pathways in the cell are inhibited by metabolites that control enzyme activity
through allosteric regulation or substrate inhibition. A good example is the
allosteric regulation of the glycolytic pathway. This catabolic pathway consumes
glucose and produces ATP, NADH and pyruvate. A key step for the regulation of
glycolysis is an early reaction in the pathway catalysed by phosphofructokinase-
1 (PFK1). When ATP levels rise, ATP binds an allosteric site in PFK1 to decrease
the rate of the enzyme reaction; glycolysis is inhibited and ATP production falls.
This negative feedback control helps maintain a steady concentration of ATP in
the cell. However, metabolic pathways are not just regulated through inhibition
since enzyme activation is equally important. With respect to PFK1, fructose 2,6-
bisphosphate and ADP are examples of metabolites that are allosteric activators.

Physiological enzyme inhibition can also be produced by specific protein


inhibitors. This mechanism occurs in the pancreas, which synthesises many
digestive precursor enzymes known as zymogens. Many of these are activated by
the trypsin protease, so it is important to inhibit the activity of trypsin in the
pancreas to prevent the organ from digesting itself. One way in which the activity
of trypsin is controlled is the production of a specific and potent trypsin inhibitor
protein in the pancreas. This inhibitor binds tightly to trypsin, preventing the
trypsin activity that would otherwise be detrimental to the organ. Although the
trypsin inhibitor is a protein, it avoids being hydrolysed as a substrate by the
protease by excluding water from trypsin's active site and destabilising the
transition state. Other examples of physiological enzyme inhibitor proteins
include the barstar inhibitor of the bacterial ribonuclease barnase and the
inhibitors of protein phosphatases.

Acetylcholinesterase inhibitors

Acetylcholinesterase (AChE) is an enzyme found in animals from insects to


humans. It is essential to nerve cell function through its mechanism of breaking
down the neurotransmitter acetylcholine into its constituents, acetate and
choline. This is somewhat unique among neurotransmitters as most, including
serotonin, dopamine, and norepinephrine, are absorbed from the synaptic cleft
rather than cleaved. A large number of AChE inhibitors are used in both medicine
and agriculture. Reversible competitive inhibitors, such as edrophonium,
physostigmine, and neostigmine, are used in the treatment of myasthenia gravis
and in anaesthesia. The carbamate pesticides are also examples of reversible
AChE inhibitors. The organophosphate insecticides such as malathion,
parathion, and chlorpyrifos irreversibly inhibit acetylcholinesterase.
To discourage seed predators, pulses contain trypsin inhibitors that interfere with
digestion.

Natural poisons

Animals and plants have evolved to synthesize a vast array of poisonous


products including secondary metabolites, peptides and proteins that can act as
inhibitors. Natural toxins are usually small organic molecules and are so diverse
that there are probably natural inhibitors for most metabolic processes The
metabolic processes targeted by natural poisons encompass more than enzymes
in metabolic pathways and can also include the inhibition of receptor, channel
and structural protein functions in a cell. For example, paclitaxel (taxol), an
organic molecule found in the Pacific yew tree, binds tightly to tubulin dimers and
inhibits their assembly into microtubules in the cytoskeleton.

Many natural poisons act as neurotoxins that can cause paralysis leading to
death and have functions for defence against predators or in hunting and
capturing prey. Some of these natural inhibitors, despite their toxic attributes, are
valuable for therapeutic uses at lower doses.[ An example of a neurotoxin are the
glycoalkaloids, from the plant species in the Solanaceae family (includes potato,
tomato and eggplant), that are acetylcholinesterase inhibitors. Inhibition of this
enzyme causes an uncontrolled increase in the acetylcholine neurotransmitter,
muscular paralysis and then death. Neurotoxicity can also result from the
inhibition of receptors; for example, atropine from deadly nightshade (Atropa
belladonna) that functions as a competitive antagonist of the muscarinic
acetylcholine receptors

Although many natural toxins are secondary metabolites, these poisons also
include peptides and proteins. An example of a toxic peptide is alpha-amanitin,
which is found in relatives of the death cap mushroom. This is a potent enzyme
inhibitor, in this case preventing the RNA polymerase II enzyme from transcribing
DNA. The algal toxin microcystin is also a peptide and is an inhibitor of protein
phosphatases. This toxin can contaminate water supplies after algal blooms and
is a known carcinogen that can also cause acute liver hemorrhage and death at
higher doses.

Proteins can also be natural poisons or antinutrients, such as the trypsin


inhibitors (discussed above) that are found in some legumes, as shown in the
figure above. A less common class of toxins are toxic enzymes: these act as
irreversible inhibitors of their target enzymes and work by chemically modifying
their substrate enzymes. An example is ricin, an extremely potent protein toxin
found in castor oil beans. This enzyme is a glycosidase that inactivates
ribosomes. Since ricin is a catalytic irreversible inhibitor, this allows just a single
molecule of ricin to kill a cell
Pharmacognosy
Pharmacognosy is the study of medicines derived from natural sources. The
American Society of Pharmacognosy[1] defines pharmacognosy as "the study of
the physical, chemical, biochemical and biological properties of drugs, drug
substances or potential drugs or drug substances of natural origin as well as the
search for new drugs from natural sources."
Contents

* 1 Introduction
o 1.1 Origin
* 2 Ethnopharmacology
* 3 Issues in phytotherapy
o 3.1 Constituents and drug synergyism
o 3.2 Herb and drug interactions
* 4 Natural products chemistry
* 5 Loss of biodiversity
* 6 Sustainable sources of plant and animal drugs
* 7 External links
* 8 References

Introduction

The word "pharmacognosy" is derived from the Greek words pharmakon (drug),
and gnosis or "knowledge". The term pharmacognosy was used for the first time
by the Austrian physician Schmidt in 1811. Originally - during the 19th century
and the beginning of the 20th century - "pharmacognosy" was used to define the
branch of medicine or commodity sciences ("Warenkunde" in German) which
dealt with drugs in their crude, or unprepared, form. Crude drugs are the dried,
unprepared material of plant, animal or mineral origin, used for medicine. The
study of these materials under the name pharmakognosie was first developed in
German-speaking areas of Europe, while other language areas often used the
older term materia medica taken from the works of Galen and Dioscorides. In
German the term drogenkunde ("science of crude drugs") is also used
synonymously.

Although most pharmacognostic studies focus on plants and medicines derived


from plants, other types of organisms are also regarded as pharmacognostically
interesting, in particular, various types of microbes (bacteria, fungi, etc.), and,
recently, various marine organisms.

Pharmacognosy is interdisciplinary, drawing on a broad spectrum of biological


and socio-scientific subjects, including botany, ethnobotany, medical
anthropology, marine biology, microbiology, herbal medicine,
chemistry,biotechnology, (phytochemistry), pharmacology, pharmaceutics,
clinical pharmacy and pharmacy practice. The contemporary study of
pharmacognosy can be divided into the fields of

* medical ethnobotany: the study of the traditional use of plants for medicinal
purposes;
* ethnopharmacology: the study of the pharmacological qualities of traditional
medicinal substances;
* the study of phytotherapy (the medicinal use of plant extracts); and
* phytochemistry, the study of chemicals derived from plants (including the
identification of new drug candidates derived from plant sources).
* Zoopharmacognosy, the process by which animals self-medicate, by
selecting and using plants, soils, and insects to treat and prevent disease.
* Pharmcognosy-Biotechnology, the synthesis of natural bioactive molecules
using biotechnology.
* Herbal interactions, the interactions of herbs with other drugs and body.
* Marine Pharmacognosy, the study of chemicals derived from marine
organisms.

Origin

The word Pharmacognosy had its debut in the early 19th century to designate the
discipline related to medicinal plants, it is derived from the Greek word
pharmakon meaning “a drug” and gnosco meaning “ to acquire a knowledge”
and as recorded by Dr. K Ganzinger.

Pharmacognosy appears again in 1815 in a small work by Crr. Anotheus ssedler


entitled Analecta Pharmacognostica.

Pharmacognosy is closely related to botany and plant chemistry and indeed, both
originated from the earlier scientific studies of medicinal plants.

As the late as the beginning of the 20th century, the subject had developed
mainly in the botanical side, being concerned with the description and
identification of drugs. Both in the whole state and in porodler, and with their
history. Commerce, collection, preparation, and storage. Such branches of
pharmacognosy are still of fundamental importance, particularly for
pharmacopoeial identification and quality control purposes, but rapid
development in other areas has enormously expanded the subject.
At the 9th congress of Italian society of pharmacognosy it was stated that current
return of phyto-therapy was clearly reflected by the increased market of such
products. In 1998 the later for Europe, reached a figure of $6 billion, with
consumption for Germany of $2.5 billion, France $1.6 billion and Italy $600 billion.
In the US, where the use of herbal products has never been as prevalent as in
continental Europe, the market for all herb sales reached a peak in 1998 of $700
billion. This welcomed the scientific investigation of a rigorous nature.

The plant kingdom still holds many species of plants containing substances of
medicinal value which have yet to be discovered. Large numbers of plants are
constantly being screened for their possible pharmacological value.

Ethnopharmacology

When studying the effectiveness of herbal medicines and other nature-derived


remedies, information on the traditional uses of certain extracts or even extract
combinations plays a key role. The lack of studies proving the use of herbs in
traditional care is especially an issue in the United States, where treatment with
herbal medicine has fallen out of use since the Second World War. Herbal
medicine has also been considered suspect since the Flexner Report of 1910 led
to the closing of the eclectic medical schools where botanical medicine was
exclusively practiced. This situation is further complicated by most herbal
studies in the latter part of the 20th Century having been published in languages
other than English such as German, Dutch, Chinese, Japanese, Korean and
Persian. As it may be more difficult to review foreign language publications,
much of the relevant information may be unavailable to English speaking
scholars. Some of the important botanicals have been incorporated into the U.S.
Food and Drug Administration (FDA) determinations of drug safety. In 1994, US
Congress passed the Dietary Supplement Health and Education Act (DSHEA),
regulating labeling and sales of herbs and other supplements. Most of the 2000
US companies making herbal or natural products[2] choose to market their
products as food supplements that do not require substantial testing.

[edit] Issues in phytotherapy

The part of pharmacognosy focusing on use of crude extracts or semi-pure


mixtures originating from nature, namely phytotherapy, is probably the best
known and also the most debated area in pharmacognosy. Although
phytotherapy is sometimes connected to alternative medicine, when critically
conducted, it may be considered the scientific study on the effects and clinical
use of herbal medicines.

Constituents and drug synergyism

One characteristic of crude drug material is that constituents may have an


opposite, moderating or enhancing effect. Hence, the final effect of any crude
drug material will be a product of the interactions between the constituents and
the effect of each constituent on its own. To effectively study the existence and
affect of such interactions, scientific studies must examine the affect that
multiple constituents, given concurrently, have on the system. Herbalists assert
that as phytopharmaceuticals rely upon synergy for their activities, plants with
high levels of active constituents like ginsenosides or hypericin may not correlate
with the strength of the herbs. In phytopharmaceutical or herbal medicine, the
therapeutic effects of herbs cannot be determined unless its active ingredient or
cofactors are identified or the herb is adminsistered as a whole. One way
manufacturers have attempted to indicate strength is to engage in
standardization to a marker compound. Companies use different markers, or
different levels of the same markers, or different methods of testing for marker
compounds. Many herbalists believe that the active ingredient in a plant is the
plant itself.

Herb and drug interactions

The Sloan Kettering Memorial Cancer Center stated, in a review of a juice


product, which had been marketed as preventing cancer, that antioxidants could
theoretically interfere with chemotherapy.[4] A recent review of the effect of
antioxidants on chemotherapy, however, found no evidence for any deleterious
effects of antioxidants on chemotherapy.[5] A study of herb drug interactions
indicated that the vast majority of drug interactions occurred in four classes of
drugs, the chief class being blood thinners, but also including protease
inhibitors, cardiac glycosides and the immuno-suppressant cyclosporin.

The major herbs that have caused interactions include St. Johns Wort, which will
counteract immunosuppressive drugs and interfere with digoxin and protease
inhibitors. A complete list can be found at:
http://www.herbological.com/images/SJW_table.pdf. The constituents of garlic,
peppermint and milk thistle have been shown to have effects on the CYP3A4
enzymes in vitro, but it is not clear whether these constituents will have the same
effect in vivo (humans).

Natural products chemistry

Most bioactive compounds of natural origin are secondary metabolites, i.e.,


species-specific chemical agents that can be grouped into various
categories[citation needed]. A typical protocol to isolate a pure chemical agent
from natural origin is bioassay-guided fractionation, meaning step-by-step
separation of extracted components based on differences in their
physicochemical properties, and assessing the biological activity, followed by
next round of separation and assaying. Typically, such work is initiated after a
given crude drug formulation (typically prepared by solvent extraction of the
natural material) is deemed "active" in a particular in vitro assay. If the end-goal
of the work at hand is to identify which one(s) of the scores or hundreds of
compounds are responsible for the observed in vitro activity, the path to that end
is fairly straightforward: 1. fractionate the crude extract, e.g. by solvent
partitioning or chromatography. 2. test the fractions thereby generated with in
vitro assay. 3. repeat steps 1) and 2) until pure, active compounds are obtained. 4.
determine structure(s) of active compound(s), typically by using spectroscopic
methods. In vitro activity does not necessarily translate to activity in humans or
other living systems. The most common means for fractionation are solvent-
solvent partitioning and chromatographic techniques such as high-performance
liquid chromatography (HPLC), medium-pressure liquid chromatography, "flash"
chromatography, open-column chromatography, vacuum-liquid chromatography
(VLC), thin-layer chromatography (TLC), with each technique being most
appropriate for a given amount of starting material. Countercurrent
chromatography (CCC) is particularly well-suited for bioassay-guided
fractionation because, as an all-liquid separation technique, concern about
irreversible loss or denaturation of active sample components is minimized. After
isolation of a pure substance, the task of elucidating its chemical structure can
be addressed. For this purpose, the most powerful methodologies available are
nuclear magnetic resonance spectroscopy (NMR) and mass spectroscopy (MS)
[citation needed]. In the case of drug discovery efforts, structure elucidation of all
components that are active in vitro is typically the end goal. In the case of
phytotherapy research, the investigator may use in vitro BAGF as a tool to
identify pharmacologically interesting or important components of the crude
drug. The work does not stop after structural identification of in vitro actives,
however. The task of "dissecting and reassembling" the crude drug one active
component at a time, in order to achieve a mechanistic understanding of how it
works in phytotherapy, is quite daunting. This is because it is simply too difficult,
from cost, time, regulatory, and even scientific perspectives, to study
experimental fractions of the crude drug in humans. In vitro assays are therefore
used to identify chemical components of the crude drug that may rationally be
expected to have a given pharmacological effect in humans, and to provide a
rational basis for standardization of a crude drug formulation to be tested in [and
sold/marketed to] humans.

Loss of biodiversity

Farnsworth for example, has found that 25% of all prescriptions dispensed from
community pharmacies in the United States from 1959 to 1980 contained active
ingredients extracted from higher plants. In some countries in Asia and Africa
80% of the population relies on traditional medicine (including herbal medicine)
for primary health care.Constituents of substances used by traditional healers,
have rarely been incorporated into modern medicine. Quinine, physostigmine, d-
tubocurarine, pilocarpine and ephedrine, have been demonstrated to have active
effects Knowledge of traditional medicinal practices is fast disappearing(?),
particularly in the Amazon, as native healers die out and are replaced by more
modern medical practitioners. Botanists and pharmacologists are racing to learn
these ancient practices[citation needed], which, like the forest plants they
employ, are also endangered

An explanation for some species loss is habitat lost due to invasive species
introduction. Herbalist David Winston has suggested that a high proportion of
nonnative species seen as invasive (kudzu, Japanese knotweed, mimosa,
lonicera, St. Johnswort and purple loosestrife) may be harvested for the domestic
herbal medicine market

Species extinction is not only due to habitat loss. Overharvesting of medicinal


species of plants and animals also contributes to species loss. This is
particularly notable in the matter of Traditional Chinese Medicine where crude
drugs of plant and animal origin are used with increasing demand. People with a
stake in TCM often seek chemical and biological alternatives to endangered
species because they realize that plants and animals lost from the wild are also
lost to medicine forever but different cultural attitudes bedevil conservation
efforts[citation needed]. Still conservation is not a new idea: Chinese advice
against overexploitation of natural medicinal species dates from at least Mencius,
a philosopher living in the 4th century BC[citation needed].

Cooperation between western conservationists and practitioners have been beset


by cultural difficulties. Westerners may emphasise urgency in matters of
conservation, while Chinese may wish for the products used in TCM to remain
publicly available. One repeated fallacy[citation needed] is that rhinoceros horn is
used as an aphrodisiac in TCM. It is, in fact, prescribed for fevers and
convulsions by TCM practitioners. There are no peer-reviewed studies showing
that this treatment is effective. In 1995 representatives of the oriental medicine
communities in Asia met with conservationists at a symposium in Hong Kong,
organized by TRAFFIC. The two groups established a clear willingness to
cooperate through dialogue and mutual understanding. This has led to several
meetings, including the 1997 First International Symposium on Endangered
Species Used in Traditional East Asian Medicine where China was among 136
nations to sign a formal resolution recognizing that the uncontrolled use of wild
species in traditional medicine threatens their survival and the continuation of
these medical practices. The resolution, drawn up by the UN Convention on
International Trade in Endangered Species (CITES), aims to initiate new
partnerships in conservation

Sustainable sources of plant and animal drugs

As species face loss of habitat or overharvesting, there have been new issues to
deal with in sourcing crude drugs. These include changes to the herb from
farming practices, substitution of species or other plants altogether, adulteration
and cross-pollination issues. For instance, ginseng which is field farmed may
have significant problems with fungus, making contamination with fungicides an
issue. This may be remedied with woods grown programs, but they are
insufficient to produce enough ginseng to meet demand. The wildcrafted
echinacea, black cohosh and American ginseng often rely upon old growth root,
often in excess of 50 years of age and it is not clear that younger stock will have
the same pharmaceutical effect. Black cohosh may be adulterated with the related
Chinese actea species, which is not the same. Ginseng may be replaced by
ginseniodes from Jiaogulan which has been stated to have a different effect than
the full panax root

The problem may be exacerbated by the growth of pills and capsules as the
preferred method of ingesting medication as they are cheaper and more available
than traditional, individually tailored prescriptions of raw medicinals but the
contents are harder to track. Seahorses are a case in point: Seahorses once had
to be of a certain size and quality before they were accepted by practitioners and
consumers. But declining availability of the preferred large, pale and smooth
seahorses has been offset by the shift towards prepackaged medicines, which
make it possible for TCM merchants to sell previously unused juvenile, spiny and
dark-coloured animals. Today almost a third of the seahorses sold in China are
prepackaged.

The farming of plant or animal species, used for medicinal purposes has caused
difficulties. Rob Parry Jones and Amanda Vincent write:

* One solution is to farm medicinal animals and plants. Chinese officials


have promoted this as a way of guaranteeing supplies as well as protecting
endangered species. And there have been some successes—notably with plant
species, such as American ginseng—which is used as a general tonic and for
chronic coughs. Red deer, too, have for centuries been farmed for their antlers,
which are used to treat impotence and general fatigue. But growing your own is
not a universal panacea. Some plants grow so slowly that cultivation in not
economically viable. Animals such as musk deer may be difficult to farm, and so
generate little profit. Seahorses are difficult to feed and plagued by disease in
captivity. Other species cannot be cultivated at all. Even when it works, farming
usually fails to match the scale of demand. Overall, cultivated TCM plants in
China supply less than 20 per cent of the required 1.6 million tonnes per annum.
Similarly, China's demand for animal products such as musk and pangolin scales
far exceeds supply from captive-bred sources.

* Farming alone can never resolve conservation concerns, as government


authorities and those who use Chinese medicine realise. For a start, consumers
often prefer ingredients taken from the wild, believing them to be more potent.
This is reflected in the price, with wild oriental ginseng fetching up to 32 times as
much as cultivated plants. Then there are welfare concerns. Bear farming in
China is particularly controversial. Around 7600 captive bears have their bile
"milked" through tubes inserted into their gall bladders. The World Society for the
Protection of Animals states that bear farming is surrounded by "appalling levels
of cruelty and neglect" . Chinese officials state that 10 000 wild bears would need
to be killed each year to produce as much bile, making bear farming the more
desirable option. The World society for the Protection of Animals, however, states
that "it is commonly believed in China that the bile from a wild bear is the most
potent, and so farming bears for their bile cannot replace the demand for the
product extracted from wild animals".

* One alternative to farming involves replacing medical ingredients from


threatened species with manufactured chemical compounds. In general, this sort
of substitution is difficult to achieve because the active ingredient is often not
known. In addition, most TCM users believe that TCM compounds may act
synergistically so several ingredients may interact to give the required effect.
Thus TCM users often people prefer the wild source. Tauro ursodeoxycholic acid,
the active ingredient of bear bile, can be synthesised and is used by some
Western doctors to treat gallstones, but many TCM consumers reject it as being
inferior to the natural substance from wild animals.

Pharmacophore
A pharmacophore was first defined by Paul Ehrlich in 1909 as "a molecular
framework that carries (phoros) the essential features responsible for a drug’s
(=pharmacon's) biological activity" (Ehrlich. Dtsch. Chem. Ges. 1909, 42: p.17). In
1977, this definition was updated by Peter Gund to "a set of structural features in
a molecule that is recognized at a receptor site and is responsible for that
molecule's biological activity" (Gund. Prog. Mol. Subcell. Biol. 1977, 5: pp 117–
143). The IUPAC definition of a pharmacophore is "an ensemble of steric and
electronic features that is necessary to ensure the optimal supramolecular
interactions with a specific biological target and to trigger (or block) its biological
response".

In modern computational chemistry, pharmacophores are used to define the


essential features of one or more molecules with the same biological activity. A
database of diverse chemical compounds can then be searched for more
molecules which share the same features located a similar distance apart from
each other.

Typical pharmacophore features are for where a molecule is hydrophobic,


aromatic, a hydrogen bond acceptor, a hydrogen bond donor, a cation, or an
anion. The features need to match different chemical groups with similar
properties, in order to identify novel ligands. Ligands receptor interactions are
typically “polar positive”, “polar negative” or “hydrophobic”. A well-defined
pharmacophore model includes both hydrophobic volumes and hydrogen bond
vectors.
Galenic formulation
Galenic formulation deals with the principles of preparing and compounding
medicines in order to optimize their absorption. Galenic formulation is named
after Claudius Galen, a 3rd Century AD Greek physician, who codified the
preparation of drugs using multiple ingredients.
Today, galenic formulation is part of pharmaceutical formulation. The
pharmaceutical formulation of a medicine has an impact on the
pharmacokinetics, pharmacodynamics and safety profile of a drug.

Pharmacopoeia
Pharmacopoeia (literally, the art of the drug compounder), in its modern technical
sense, is a book containing directions for the identification of samples and the
preparation of compound medicines, and published by the authority of a
government or a medical or pharmaceutical society

In a broader sense is a reference work for pharmaceutical drug specifications.

The name has also been applied to similar compendia issued by private
individuals.
Contents

* 1 History
o 1.1 National Pharmacopoeia
o 1.2 International Pharmacopoeia
* 2 Preparations
* 3 See also
* 4 References
* 5 External links

History

Pliny’s pharmacopoeia is considered to be the cradle of pharmacotherapy.[1]


Pedanius Dioscorides is famous for writing a five volume book in his
native Greek Περί ύλης ιατρικής (De Materia Medica - in the Latin
translation) that is a precursor to all modern pharmacopoeias, and
is one of the most influential herbal books in history. In fact it remained in
use until about CE 1600.
Some of the earliest pharmacopoeia books were written by Persian physicians.[3]
These included The Canon of Medicine of Avicenna in 1025, and other
pharmacopoeia books by Abu-Rayhan Biruni in the 11th century,[4] Ibn Zuhr
(Avenzoar) in the 12th century (and printed in 1491),[5] and Ibn Baytar in the 14th
century

The first work of the kind published under government authority appears to have
been that of Nuremberg in 1542; a passing student named Valerius Cordus
showed a collection of medical receipts, which he had selected from the writings
of the most eminent medical authorities, to the physicians of the town, who urged
him to print it for the benefit of the apothecaries, and obtained for his work the
sanction of the senatus.

An earlier work, known as the Antidotarium Florentinum, had been published


under the authority of the college of medicine of Florence.

The term pharmacopoeia first appears as a distinct title in a work published at


Basel in 1561 by Dr A. Foes, but does not appear to have come into general use
until the beginning of the 17th century.

Before 1542 the works principally used by apothecaries were the treatises on
simples by Avicenna and Serapion; the De synonymis and Quid pro quo of Simon
Januensis; the Liber servitoris of Bulchasim Ben Aberazerim, which described
the preparations made from plants, animals and minerals, and was the type of the
chemical portion of modern pharmacopoeias; and the Antidotarium of Nicolaus
de Salerno, containing Galenical compounds arranged alphabetically. Of this, last
work there were two editions in use — Nicolaus magnus and Nicolaus parvus: in
the later several of the compounds described in the large edition were omitted
and the formulae given on a smaller scale.

Until 1617 such drugs and medicines as were in common use were sold in
England by the apothecaries and grocers. In that year the apothecaries obtained
a separate charter, and it was enacted that no grocer should keep an
apothecary’s shop. The preparation of physicians’ prescriptions was thus
confined to the apothecaries, upon whom pressure was brought to bear to make
them dispense accurately, by the issue of a pharmacopoeia in May 1618 by the
College of Physicians, and by the power which the wardens of the apothecaries
received in common with the censors of the College of Physicians of examining
the shops of apothecaries within 7 m. of London and destroying all the
compounds which they found unfaithfully prepared. This, the first authorized
London Pharmacopoeia, was selected chiefly from the works of Mezue and
Nicolaus de Salerno, but it was found to be so full of errors that the whole edition
was cancelled, and a fresh edition was published in the following December. At
this period the compounds employed in medicine were often heterogeneous
mixtures, some of which contained from 20 to 70, or more, ingredients, while a
large number of simples were used in consequence of the same substance being
supposed to possess different qualities according to the source from which it
was derived. Thus crabs’ eyes (i.e., gastroliths), pearls, oyster-shells and coral
were supposed to have different properties. Among other ingredients entering
into some of these formulae were the excrements of human beings, dogs, mice,
geese and other animals, calculi, human skull and moss growing on it, blind
puppies, earthworms, etc. Although other editions of the London Pharmacopoeia
were issued in 1621, 1632, 1639 and 1677, it was not until the edition of 1721,
published under the auspices of Sir Hans Sloane, that any important alterations
were made. In this issue many of the ridiculous remedies previously in use were
omitted, although a good number were still retained, such as dogs’ excrement,
earthworms, and moss from the human skull; the botanical names of herbal
remedies were for the first time added to the official ones; the simple distilled
waters were ordered of a uniform strength; sweetened spirits, cordials and
ratifias were omitted as well as several compounds no longer used in London,
although still in vogue elsewhere. A great improvement was effected in the
edition published in 1746, in which only those preparations were retained which
had received the approval of the majority of the pharmacopoeia committee; to
these was added a list of those drugs only which were supposed to be the most
efficacious. An attempt was made to simplify further the older formulae by the
rejection of superfluous ingredients. In the edition published in 1788 the tendency
to simplify was carried out to a much greater extent, and the extremely compound
medicines which had formed the principal remedies of physicians for 2000 years
were discarded, while a few powerful drugs which had been considered too
dangerous to be included in the Pharmacopoeia of 1765 were restored to their
previous position. In 1809 the French chemical nomenclature was adopted, and in
1815 a corrected impression of the same was issued. Subsequent editions were
published in 1824, 1836 and 1851.

The first Edinburgh Pharmacopoeia was published in 1699 and the last in 1841;
the first Dublin Pharmacopoeia in 1807 and the last in 1850.

National Pharmacopoeia

The preparations contained in these three pharmacopoeias were not all uniform
in strength, a source of much inconvenience and danger to the public, when
powerful preparations such as dilute hydrocyanic acid were ordered in the one
country and dispensed according to the national pharmacopoeia in another. As a
result, the Medical Act of 1858 ordained that the General Medical Council should
publish a book containing a list of medicines and compounds, to be called the
British Pharmacopoeia, which would be a substitute throughout Great Britain and
Ireland for the separate pharmacopoeias. Hitherto these had been published in
Latin. The first British Pharmacopoeia was published in the English language in
1864, but gave such general dissatisfaction both to the medical profession and to
chemists and druggists that the General Medical Council brought out a new and
amended edition in 1867. This dissatisfaction was probably owing partly to the
fact that the majority of the compilers of the work were not engaged in the
practice of pharmacy, and therefore competent rather to decide upon the kind of
preparations required than upon the method of their manufacture. The necessity
for this element in the construction of a pharmacopoeia is now fully recognized in
other countries, in most of which pharmaceutical chemists are represented on
the committee for the preparation of the legally recognized manuals.

There are national and international pharmacopoeias, like the EU and the US
pharmacopoeias. All the pharmacopoeias were issued under the authority of
government, and their instructions have the force of law in their respective
territories, except that of the United States, which was prepared by
commissioners appointed by medical and pharmaceutical societies, and has no
other authority, although generally accepted as the national textbook.

International Pharmacopoeia

Increased facilities for travel have brought into greater prominence the
importance of an approach to uniformity in the formulae of the more powerful
remedies, in order to avoid danger to patients when a prescription is dispensed in
a different country from that in which it was written. Attempts have been made by
international pharmaceutical and medical conferences to settle a basis on which
an international pharmacopoeia could be prepared, but due to national jealousies
and the attempt to include too many preparations nothing has yet been achieved.

Nonetheless, some progress has been made under the banner of the ICH (The
International Conference on Harmonisation of Technical Requirements for
Registration of Pharmaceuticals for Human Use:www.ich.org), a tri-regional
organisation that represents the drug regulatory authorities of the European
Union, Japan and the United States. Representatives from the Pharmacopoeias of
these three regions have met twice yearly since 1990 in the Pharmacopoeial
Discussion Group to try to work towards "compendial harmonisation"’. Specific
monographs are proposed, and if accepted, proceed through stages of review
and consultation leading to adoption of a common monograph that provides a
common set of tests and specifications for a specific material. Not surprisingly,
this is a slow process.

Preparations

The rapid increase in medical and pharmaceutical knowledge renders necessary


frequent new editions of the national pharmacopoeias, the office of which is to
furnish definite formulae for preparations that have already come into extensive
use in medical practice, so as to ensure uniformity of strength, and to give the
characters and tests by which their purity and potency may be determined. But
each new edition requires several years to carry out numerous experiments for
devising suitable formulae, so that the current Pharmacopoeia can never be quite
up to date. This difficulty has hitherto been met by the publication of such
nonofficial formularies as Squire's Companion to the Pharmacopoeia and
Martindale: The complete drug reference (formerly Martindale's : The Extra
Pharmacopoeia), in which all new remedies and their preparations, uses and
doses are recorded, and in the former the varying strengths of the same
preparations in the different pharmacopoeias are also compared (Squire's was
incorporated into Martindal in 1952). The need of such works to supplement the
Pharmacopoeia is shown by the fact that they are even more largely used than
the Pharmacopoeia itself, the first issued in 18 editions and the second in 13
editions at comparatively short intervals. In the UK, the task of elaborating a new
Pharmacopoeia is entrusted to a body of a purely medical character, and legally
the pharmacist has not, contrary to the practice in other countries, a voice in the
matter, notwithstanding the fact that, although the medical practitioner is
naturally the best judge of the drug or preparations that will afford the best
therapeutic result, he is not so competent as the pharmacist to say how that
preparation can be produced in the most effective and satisfactory manner, nor
how the purity of drugs can be tested.

The change occurred with the fourth edition of the British Pharmacopoeia in
1898. A committee of the Royal Pharmaceutical Society of Great Britain was
appointed at the request of the General Medical Council to advise on
pharmaceutical matters. A census of prescriptions was taken to ascertain the
relative frequency with which different preparations and drugs were used in
prescriptions, and suggestions and criticisms were sought from various medical
and pharmaceutical bodies across the British Empire. As regards the purely
pharmaceutical part of the work a committee of reference in pharmacy,
nominated by the pharmaceutical societies of Great Britain and Ireland (as they
were then), was appointed to report to the Pharmacopoeia Committee of the
Medical Council.

Some difficulty has arisen since the passing of the Adulteration of Food and
Drugs Act[citation needed] concerning the use of the Pharmacopoeia as a legal
standard for the drugs and preparations contained in it. The Pharmacopoeia is
defined in the preface as only "intended to afford to the members of the medical
profession and those engaged in the preparation of medicines throughout the
British Empire one uniform standard and guide whereby the nature and
composition of, substances to be used in medicine may be ascertained and
determined." It is obvious that it cannot be an encyclopaedia of substances used
in medicine, and can only be used as a standard for the substances and
preparations contained in it, and for no others. It has been held in the Divisional
Courts (Dickins v. Randerson) that the Pharmacopoeia is a standard for official
preparations asked for under their pharmacopoeial name. But there are many
substances in the Pharmacopoeia which are not only employed in medicine, but
have other uses, such as sulphur, gum benzoin, tragacanth, gum arabic,
ammonium carbonate, beeswax, oil of turpentine, linseed oil, and for these a
commercial standard of purity as distinct from a medicinal one is needed, since
the preparations used in medicine should be of the highest possible degree of
purity obtainable, and this standard would be too high and too expensive for
ordinary purposes. The use of trade synonyms in the Pharmacopoeia, such as
saltpetre for purified potassium nitrate, and milk of sulphur for precipitated
sulphur, is partly answerable for this difficulty, and has proved to be a mistake,
since it affords ground for legal prosecution if a chemist sells a drug of ordinary
commercial purity for trade purposes, instead of the purified preparation which is
official in the Pharmacopoeia for medicinal use. This would not be the case if the
trade synonym were omitted. For many drugs and chemicals not in the
Pharmacopoeia there is no standard of purity that can be used under the
Adulteration of Food and Drugs Act, and for these, as well as for the commercial
quality of those drugs and essential oils which are also in the Pharmacopoeia, a
legal standard of commercial purity is much needed. This subject formed the
basis of discussion at several meetings of the Pharmaceutical Society, and the
results have been embodied in a work entitled Suggested Standards for Foods
and Drugs, by C. G. Moor, which indicates the average degree of purity of many
drugs and chemicals used in the arts, as well as the highest degree of purity
obtainable in commerce of those used in medicine.

An important step has also been taken in this direction by the publication under
the authority of the Council of the Pharmaceutical Society of Great Britain of the
British Pharmaceutical Codex, in which the characters of and tests for the purity
of many nonofficial drugs and preparations are given as well as the character of
many glandular preparations and antitoxins that have come into use in medicine,
but have not yet been introduced into the Pharmacopoeia. This work may also
possibly serve as a standard under the Adulteration of Food and Drugs Act for
the purity and strength of drugs not included in the Pharmacopoeia and as a
standard for the commercial grade of purity of those in the Pharmacopoeia which
are used for non-medical purposes.

Another legal difficulty connected with modern pharmacopoeias is the inclusion


in some of them of synthetic chemical remedies, the processes for preparing
which have been patented, whilst the substances are sold under trade-mark
names such as verona. The scientific chemical name is often long and unwieldy,
and the physician prefers when writing a prescription to use the shorter name
under which it is sold by the patentees. In this case the pharmacist is compelled
to use the more expensive patented article and the patient complains of the price.
If he uses the same article under its pharmacopoeial name when the patented
article is prescribed s/he lays oneself open to prosecution by the patentee for
infringement of patent rights. The only plan, therefore, is for the physician to use
the chemical name (which cannot be patented) as given in the Pharmacopoeia, or
for those synthetic remedies not included in the Pharmacopoeia, to use the
scientific and chemical name given in the British Pharmaceutical Codex.
Pharmaceutical formulation
Pharmaceutical formulation, in pharmaceutics, is the process in which different
chemical substances, including the active drug, are combined to produce a final
medicinal product.
Contents

* 1 Stages and timeline


* 2 Oral formulations
o 2.1 Tablet form
o 2.2 Capsule form
* 3 Topical medication forms
* 4 See also
* 5 References
* 6 External links

Stages and timeline

Formulation studies involve developing a preparation of the drug which is both


stable and acceptable to the patient. For orally taken drugs, this usually involves
incorporating the drug into a tablet or a capsule. It is important to appreciate that
a tablet contains a variety of other substances apart from the drug itself, and
studies have to be carried out to ensure that the drug is compatible with these
other substances.

Preformulation involves the characterization of a drug's physical, chemical, and


mechanical properties in order to choose what other ingredients should be used
in the preparation. In dealing with protein pre-formulation, the important aspect is
to understand the solution behavior of a given protein under a variety of stress
conditions such as freeze/thaw, temperature, shear stress among others to
identify mechanisms of degradation and therefore its mitigation.

Formulation studies then consider such factors as particle size, polymorphism,


pH, and solubility, as all of these can influence bioavailability and hence the
activity of a drug. The drug must be combined with inactive additives by a
method which ensures that the quantity of drug present is consistent in each
dosage unit e.g. each tablet. The dosage should have a uniform appearance, with
an acceptable taste, tablet hardness, or capsule disintegration.
It is unlikely that formulation studies will be complete by the time clinical trials
commence. This means that simple preparations are developed initially for use in
phase I clinical trials. These typically consist of hand-filled capsules containing a
small amount of the drug and a diluent. Proof the long-term stability of these
formulations is not required, as they will be used (tested) in a matter of days.
Consideration has to be given to what is called the drug load - the ratio of the
active drug to the total contents of the dose. A low drug load may cause
homogeneity problems. A high drug load may pose flow problems or require
large capsules if the compound has a low bulk density.

By the time phase III clinical trials are reached, the formulation of the drug should
have been developed to be close to the preparation that will ultimately be used in
the market. A knowledge of stability is essential by this stage, and conditions
must have been developed to ensure that the drug is stable in the preparation. If
the drug proves unstable, it will invalidate the results from clinical trials since it
would be impossible to know what the administered dose actually was. Stability
studies are carried out to test whether temperature, humidity, oxidation, or
photolysis (ultraviolet light or visible light) have any effect, and the preparation is
analysed to see if any degradation products have been formed.

It is also important to check whether there are any unwanted interactions


between the preparation and the container. If a plastic container is used, tests are
carried out to see whether any of the ingredients become adsorbed on to the
plastic, and whether any plasticizers, lubricants, pigments, or stabilizers leach
out of the plastic into the preparation. Even the adhesives for the container label
need to be tested, to ensure they do not leach through the plastic container into
the preparation.

Oral formulations

The way a drug is formulated can avoid some of the problems associated with
oral administration.

Drugs are normally taken orally as tablets or capsules.

The drug (active substance) itself needs to be soluble in aqueous solution at a


controlled rate. Such factors as particle size and crystal form can significantly
affect dissolution. Fast dissolution is not always ideal. For example, slow
dissolution rates can prolong the duration of action or avoid initial high plasma
levels. Treatment of active ingredient by special way as spherical crystallization
can have some advantages for drug formulation.

Tablet form

A tablet is usually a compressed preparation that contains:


* 5-10% of the drug (active substance);
* 80% of fillers, disintegrants, lubricants, glidants, and binders; and
* 10% of compounds which ensure easy disintegration, disaggregation, and
dissolution of the tablet in the stomach or the intestine.

The disintegration time can be modified for a rapid effect or for sustained release.

Special coatings can make the tablet resistant to the stomach acids such that it
only disintegrates in the duodenum as a result of enzyme action or alkaline pH.

Pills can be coated with sugar, varnish, or wax to diguise the taste.

Some tablets are designed with an osmotically active core, surrounded by an


impermeable membrane with a pore in it. This allows the drug to percolate out
from the tablet at a constant rate as the tablet moves through the digestive tract.

Capsule form

A capsule is a gelatinous envelope enclosing the active substance. Capsules can


be designed to remain intact for some hours after ingestion in order to delay
absorption. They may also contain a mixture of slow- and fast-release particles to
produce rapid and sustained absorption in the same dose.

Topical medication forms

* Cream - Emulsion of oil and water in approximately equal proportions.


Penetrates stratum corneum outer layer of skin well.

* Ointment - Combines oil (80%) and water (20%). Effective barrier against
moisture loss.

* Gel - Liquefies upon contact with the skin.

* Paste - Combines three agents - oil, water, and powder; an ointment in which
a powder is suspended.

* Powder

Dosage form
A dosage form (DF) is the physical form of a dose of a chemical compound used
as a drug or medication intended for administration or consumption. Common
dosage forms include pill, tablet, or capsule, drink or syrup, aerosol or inhaler,
liquid injection, pure powder or solid crystal (e.g., via oral ingestion or freebase
smoking), and natural or herbal form such as plant or or food of sorts, among
many others. Notably, the route of administration (ROA) for drug delivery is
dependent on the dosage form of the substance in question.

Various dosage forms may exist for a single particular drug, since different
medical conditions can warrant different routes of administration. For example,
persistent nausea and emesis or vomiting may make it difficult to use an oral
dosage form, and in such a case, it may be necessary to utilize an alternate route
such as inhalational, buccal, sublingual, nasal, suppository, or parenteral instead.

Additionally, a specific dosage form may be a requirement for certain kinds of


drugs, as there may be issues with various factors like chemical stability or
pharmacokinetics. As an example, insulin cannot be given orally because upon
being administered in this manner, it is extensively metabolized in the
gastrointestinal tract (GIT) before reaching the blood stream, and is thereby
incapable of sufficiently reaching its therapeutic target destinations.
Contents

* 1 Types
o 1.1 Oral
o 1.2 Inhalational
o 1.3 Parenteral Injection
o 1.4 Topical
o 1.5 Suppository
* 2 See Also
* 3 References
* 4 External Links

Types
Oral

* Pill, tablet, or capsule


* Specialty tablet like buccal, sublingual, or orally-disintegrating
* Thin film (e.g., Listerine PocketPaks)
* Liquid solution or suspension (e.g., drink or syrup)
* Powder or liquid or solid crystals
* Natural or herbal plant, seed, or food of sorts (e.g., marijuana such as that
found in "special brownies")

Inhalational

* Aerosol
* Inhaler
* Nebulizer
* Smoking (often in natural herb or freebase powder form (e.g., tobacco or
marijuana and cocaine or methamphetamine, respectively))
* Vaporizer (usually to vaporize natural herbs like marijuana)

Parenteral Injection

* Intradermal (ID)
* Intramuscular (IM)
* Intraosseous (IR)
* Intraperitoneal (IP)
* Intravenous (IV)
* Subcutaneous (SC)

Topical

* Cream, gel, liniment or balm, lotion, or ointment, etc


* Ear drops (optic)
* Eye drops (ophthalmic)
* Skin patch (transdermal)

Suppository

* Rectal (e.g., enema)


* Vaginal (e.g., douche, pessary, etc)

Route of administration
A route of administration in pharmacology and toxicology is the path by which a
drug, fluid, poison, or other substance is brought into contact with the body.

A substance must be transported from the site of entry to the part of the body
where its action is desired to take place (even if this only means penetration
through the stratum corneum into the skin). Using the body's transport
mechanisms for this purpose, however, is not trivial. The pharmacokinetic
properties of a drug (that is, those related to processes of uptake, distribution,
and elimination) are critically influenced by the route of administration.
Contents
* 1 Classification
o 1.1 Topical
o 1.2 Enteral
o 1.3 Parenteral by injection or infusion
o 1.4 Other parenteral
o 1.5 Other
* 2 Advantages and disadvantages
o 2.1 Inhalation
o 2.2 Injection
* 3 Uses
* 4 Notes
* 5 See also
* 6 References
* 7 External links

Classification

Routes of administration can broadly be divided into:

* topical: local effect, substance is applied directly where its action is desired.
* enteral: desired effect is systemic (non-local), substance is given via the
digestive tract.
* parenteral: desired effect is systemic, substance is given by routes other than
the digestive tract.

The U.S. Food and Drug Administration recognizes 111 distinct routes of
administration. The following is a brief list of some routes of administration.

Topical

* epicutaneous (application onto the skin), e.g. allergy testing, typical local
anesthesia
* inhalational, e.g. asthma medications
* enema, e.g. contrast media for imaging of the bowel
* eye drops (onto the conjunctiva), e.g. antibiotics for conjunctivitis
* ear drops - such as antibiotics and corticosteroids for otitis externa
* intranasal route (into the nose), e.g. decongestant nasal sprays. Nasal
administration can also be used for systemic effect. This is related to the
transmucosal route through a mucous membrane via insufflation.
* vaginal, e.g. topical estrogens, antibacterials

Enteral

Enteral is any form of administration that involves any part of the gastrointestinal
tract:
* by mouth (orally), many drugs as tablets, capsules, or drops
* by gastric feeding tube, duodenal feeding tube, or gastrostomy, many drugs
and enteral nutrition
* rectally, various drugs in suppository or enema form

Parenteral by injection or infusion

* intravenous (into a vein), e.g. many drugs, total parenteral nutrition


* intraarterial (into an artery), e.g. vasodilator drugs in the treatment of
vasospasm and thrombolytic drugs for treatment of embolism
* intramuscular (into a muscle), e.g. many vaccines, antibiotics, and long-term
psychoactive agents. Recreationally the colloquial term 'muscling' is used.
* intracerebral (into the cerebrum) direct injection into the brain. Used in
experimental research of chemicals[3] and as a treatment for malignancies of the
brain.[4] The intracerebral route can also interrupt the blood brain barrier from
holding up against subsequent routes.
* intracerebroventricular (into the cerebral ventricles) administration into the
ventricular system of the brain. One use is as a last line of opioid treatment for
terminal cancer patients with intractable cancer pain.[6]
* intracardiac (into the heart), e.g. adrenaline during cardiopulmonary
resuscitation (no longer commonly performed)
* subcutaneous (under the skin), e.g. insulin, a slang term for this method of
administration is skin popping (usually done with recreational drugs)
* intraosseous infusion (into the bone marrow) is, in effect, an indirect
intravenous access because the bone marrow drains directly into the venous
system. This route is occasionally used for drugs and fluids in emergency
medicine and paediatrics when intravenous access is difficult.
* intradermal, (into the skin itself) is used for skin testing some allergens, and
also for mantoux test for Tuberculosis
* intrathecal (into the spinal canal) is most commonly used for spinal
anesthesia and chemotherapy
* intraperitoneal, (infusion or injection into the peritoneum) e.g. peritoneal
dialysis
* Intravesical infusion is into the urinary bladder.
* Intracavernosal injection is into the base of the penis.

Other parenteral

* transdermal (diffusion through the intact skin), e.g. transdermal patches such
as fentanyl in pain therapy, nicotine patches for treatment of addiction
* transmucosal (diffusion through a mucous membrane), e.g. insufflation
(snorting) of cocaine, sublingual, i.e. under the tongue, nitroglycerine, buccal
(absorbed through cheek near gumline), vaginal suppositories
* inhalational, e.g. inhalational anesthetics
* intracisternal: given between the first and second cervical vertebrae – used to
withdraw cerebrospinal fluid for dignostic purposes.

Other

* epidural (synonym: peridural) (injection or infusion into the epidural space),


e.g. epidural anesthesia
* intravitreal, through the eye

Advantages and disadvantages

There are advantages and disadvantages to each route of administration

[edit] Inhalation

Advantages

* Fastest method, 7–10 seconds for the drug to reach the brain
* User can titrate (regulate the amount of drug they are receiving)

Disadvantages

* Typically a more addictive route of administration because it is the fastest,


leading to instant gratification. In addition, drugs taken by inhalation do not stay
in the bloodstream for as long, causing the user to redose more quickly and
intensifying the association between consuming the drug and it's effects.
* Difficulties in regulating the exact amount of dosage
* Patient having difficulties in giving themselves a drug by inhaler

Injection

Injection incompasses intravenous (IV), intramuscular (IM), and subcutaneous


(subcut) (sub-Q no longer a safe abbreviation[why?])

Advantages

* Fast: 15–30 seconds for IV, 3–5 minutes for IM and subcutaneous
* 100% bioavailability
* suitable for drugs not absorbed by the gut or those that are too irritant (anti-
cancer)
* One injection can be formulated to last days or even months, e.g., Depo-
Provera, a birth control shot that works for three months
* IV can deliver continuous medication, e.g., morphine for patients in
continuous pain, or saline drip for people needing fluids

Disadvantages
* Onset of action is quick, hence more risk of addiction when it comes to
injecting drugs of abuse
* Patients are not typically able to self-administer
* Belonephobia, the fear of needles and injection.
* If needles are shared, there is risk of HIV and other infectious diseases
* It is the most dangerous route of administration because it bypasses most of
the body's natural defenses, exposing the user to health problems such as
hepatitis, abscesses, infections, and undissolved particles or
additives/contaminants
* If not done properly, potentially fatal air boluses (bubbles) can occur.
* Need for strict asepsis

Uses

Some routes can be used for topical as well as systemic purposes, depending on
the circumstances. For example, inhalation of asthma drugs is targeted at the
airways (topical effect), whereas inhalation of volatile anesthetics is targeted at
the brain (systemic effect).

On the other hand, identical drugs can produce different results depending on the
route of administration. For example, some drugs are not significantly absorbed
into the bloodstream from the gastrointestinal tract and their action after enteral
administration is therefore different from that after parenteral administration. This
can be illustrated by the action of naloxone (Narcan), an antagonist of opiates
such as morphine. Naloxone counteracts opiate action in the central nervous
system when given intravenously and is therefore used in the treatment of opiate
overdose. The same drug, when swallowed, acts exclusively on the bowels; it is
here used to treat constipation under opiate pain therapy and does not affect the
pain-reducing effect of the opiate.

Enteral routes are generally the most convenient for the patient, as no punctures
or sterile procedures are necessary. Enteral medications are therefore often
preferred in the treatment of chronic disease. However, some drugs can not be
used enterally because their absorption in the digestive tract is low or
unpredictable. Transdermal administration is a comfortable alternative; there are,
however, only a few drug preparations are suitable for transdermal
administration.

In acute situations, in emergency medicine and intensive care medicine, drugs


are most often given intravenously. This is the most reliable route, as in acutely ill
patients the absorption of substances from the tissues and from the digestive
tract can often be unpredictable due to altered blood flow or bowel motility.

Notes

1. ^ "Exposition" may be a more appropriate term in toxicology.


"Administration", however, can be used for deliberate substance use.
2. ^ Fenway Community Health
3. ^ MDMA (ecstasy) metabolites and neurotoxicity: No occurrence of MDMA
neurotoxicity from metabolites when injected directly into brain, study shows.
4. ^ A potential application for the intracerebral injection of drugs entrapped
within liposomes in the treatment of human cerebral gliomas.
5. ^ Blood-brain barrier changes following intracerebral injection
of human recombinant tumor necrosis factor-α in the rat
6. ^ Acute Decreases in Cerebrospinal Fluid Glutathione Levels after
Intracerebroventricular Morphine for Cancer Pain

Injection (medicine)
An injection (often referred to as a "shot") is an infusion method of putting liquid
into the body, usually with a hollow needle and a syringe which is pierced
through the skin to a sufficient depth for the material to be forced into the body.
An injection follows a parenteral route of administration, that is, administered
other than through the digestive tract.
Hypodermic syringe injection

There are several methods of injection or infusion, including intradermal,


subcutaneous, intramuscular, intravenous, intraosseous, and intraperitoneal.
Long-acting forms of subcutaneous/intramuscular injections are available for
various drugs, and are called depot injections.
Contents

* 1 Intramuscular injection
* 2 Depot injection
* 3 Hypodermic injections in nature
* 4 Injection pain
* 5 References
* 6 See also
* 7 External links

Intramuscular injection
Main article: Intramuscular injection

In an intramuscular injection, the medication is delivered directly into a muscle.


Many vaccines are administered intramuscularly, as well as codeine,
metoclopramide, and many other medications. Many drugs injected
intramuscularly are absorbed into the muscle fairly quickly, while others are more
gradual.

Generally, intramuscular injections are not self-administered, but rather by a


trained medical professional. However, prescribed self-administered
intramuscular injections are becoming more common for patients who require
these injections routinely.

Depot injection

A depot injection is an injection, usually subcutaneous or intramuscular, of a


pharmacological agent which releases its active compound in a consistent way
over a long period of time. Depot injections are usually either solid or oil-based.
Depot injections may be available as certain forms of a drug, such as decanoate
salts or esters. Examples of depot injections include Depo Provera and
haloperidol decanoate.

The advantages of using a long-acting depot injection include increased


medication compliance due to reduction in the frequency of dosing, as well as
more consistent serum concentrations. A significant disadvantage is that the
drug is not immediately reversible, since it is slowly released.

Hypodermic injections in nature

Various animals, and some plants, have been injecting for various reasons long
before humans began doing so. This process is often called stinging. Some
examples include:

* Snakes, wasps, scorpions: poison, to kill prey and self-defense.


* Some bees: poison, for self-defense and to defend their nests.
* Cnidaria (jellyfish, etc.): poison, to kill prey.
* Stinging nettles: poison, to try to avoid being eaten.

Injection pain

The pain of an injection may be lessened by prior application of ice or topical


anesthetic or simultaneous pinching of the skin. Recent studies suggest that
forced coughing during an injection stimulates a transient rise in blood pressure
which inhibits the perception of pain. Sometimes, as with an amniocentesis, a
local anesthetic is given.[1] The most common technique to reduce the pain of an
injection is simply to distract the patient.
Drug injection
Drug injection of recreational drugs is a method of introducing the drug into the
body with a hollow needle and a syringe which is pierced through the skin into
the body (usually intravenous, but also intramuscular or subcutaneous). This act
is often colloquially referred to as shooting or banging. Although there are
various methods of taking drugs, injection is favoured by some users as the full
effects of the drug are experienced very quickly, typically in five to ten seconds. It
also bypasses first-pass metabolism in the liver, resulting in a higher
bioavailability for many drugs than oral ingestion would (so users get a stronger
effect from the same amount of the drug). This shorter, more intense high can
lead to a dependency, both physical and psychological, developing more quickly
than with other methods of taking drugs.

A wide variety of drugs are injected, among the most popular in many countries
are morphine, heroin, cocaine, amphetamine and methamphetamine. Prescription
drugs, including tablets, capsules, or even liquids or suppositories, are also
sometimes injected, especially prescription opioids, since many opioid addicts
already inject heroin. Injecting preparations not intended for this purpose is
particularly dangerous because of the presence of excipients (fillers), which can
cause blood clots. Injecting codeine into the bloodstream directly is dangerous
because it causes a rapid histamine release, which can lead to potentially fatal
anaphylaxis and pulmonary edema. Dihydrocodeine, hydrocodone, nicocodeine,
thebaine and other codeine-based products also carry a moderate risk in this
case.[citation needed]

Some manufacturers add the narcotic antagonist naloxone or the anticholinergics


atropine and homatropine (in lower than therapeutic doses) to their pills to
prevent injection. Unlike naloxone, atropine does indeed help morphine and other
narcotics combat neuralgia. The atropine may very well not present a problem,
and there is the possibility of atropine content reduction of soluble tablets by
placing them on an ink blotter with a drop of water on top, then preparing a shot
from the remainder of the pill. Canada and many other countries prohibit
manufacturers from including secondary active ingredients for the above reason;
their Talwin PX does not contain naloxone. However, as a narcotic agonist-
antagonist, pentazocine and its relatives can cause withdrawal in those
physically dependent upon narcotics.

Of all the ways to ingest drugs, injection, by far, carries the most risks as it
bypasses the body's natural filtering mechanisms against viruses, bacteria and
foreign objects. There will always be much less risk of overdose, disease,
infections and health problems with alternatives to injecting, such as smoking,
insufflation (snorting or nasal ingestion), or swallowing.
Viruses such as HIV and hepatitis C are prevalent among IV drug users in many
countries, mostly due to small groups sharing injection equipment combined with
a lack of proper sterilization. Other health problems arise from poor hygiene and
injection technique (be it IV, IM, or SC), such as cotton fever, phlebitis,
abscesses, vein collapse, ulcers, malaria, gas gangrene, tetanus, septicaemia,
thrombosis, embolism and all results thereof. Drug injection is also commonly a
component in HIV-related syndemics. Fragments from injection of pills are known
to clog the small blood vessels of the lungs, brain and elsewhere. Hitting arteries
and nerves is dangerous, painful, and presents its own similar spectrum of
problems.
Contents

* 1 History
* 2 Advantages
* 3 Disadvantages
* 4 Preparation of intravenous injection
* 5 Harm reduction
* 6 Safer injection of illicit drugs
* 7 Epidemiology
* 8 Alternatives to injection
* 9 See also
* 10 References
* 11 External links

History

IV drug use is a relatively recent phenomenon arising from the invention of re-
usable syringes and the synthesis of chemically pure morphine and cocaine.

It was noted that administering drugs intravenously strengthened their effect and
since such drugs as heroin and cocaine were already being used to treat a wide
variety of ailments, many patients were given injections of 'hard drugs' for such
ailments as alcoholism and depression.

By the time of Aleister Crowley[citation needed] intravenous drug culture already


had a small, but loyal following. Sir Arthur Conan Doyle writes that Sherlock
Holmes used to inject cocaine to occupy his mind between cases.

Advantages

There are a variety of reasons why drugs would be injected rather than taken
through other methods.

* Increased effect — Injecting a drug intravenously means that more of the drug
will reach the brain more quickly. This also means that the drug will have a very
strong and rapid onset (or rush).
* More efficient usage — Injection ensures that all of the drug will be absorbed.
* Bypasses the digestive system — Some people with sensitive stomachs find
it very unpleasant to swallow drugs because of persistent cramps or nausea.
* Does not harm the lungs or mucous membranes — The mucous membranes
can be permanently damaged by habitual insufflation (snorting), and the lungs
can be damaged by smoking.

Disadvantages

In addition to general problems associated with any IV drug administration (see


risks of IV therapy) there are some specific problems associated with the informal
injection of drugs by non-professionals.

* Increased chance of infection — This is generally a twofold problem.


o Needle sharing transmits blood-borne diseases between users.
o Abscessed infections of injection sites are caused by lack of hygiene and
a lack of aseptic technique.

In addition, the use of cotton to filter some drugs can lead to cotton fever.

* Increased chance of overdose — Because IV injection delivers a dose of drug


straight into the bloodstream it is harder to gauge how much to use (as opposed
to smoking or snorting where the dose can be increased incrementally until the
desired effect is achieved). In addition, because of the rapid onset, overdose can
occur very quickly, requiring immediate action.
* Scarring of the peripheral veins — This arises from the use of blunt injecting
equipment. This is particularly common with users who have been injecting while
in jail and re-use disposable syringes sometimes hundreds of times. IV drug use
for an extended period may result in collapsed veins. Though rotating sites and
allowing time to heal before reuse may decrease the likelihood of this occurring,
collapse of peripheral veins may still occur with prolonged IV drug use. IV drug
users are among the most difficult patient populations to obtain blood-specimens
from because of peripheral venous scarring. The darkening of the veins due to
scarring and toxin buildup produce tracks along the length of the veins and are
known as track marks.
* Increased chance of addiction — The heightened effect of administering
drugs intravenously can make the chances of addiction more likely.
* Needle phobia — Quite a number of people have an intense aversion to
needles which, in extreme cases, is called trypanophobia and can make them feel
nauseous or faint.
* Social stigma — In many societies there is a social stigma attached to IV drug
use, in addition to the more general stigma around illegal drug use and addiction.
Many people feel that it is somehow "unclean" to take drugs in such a manner,
even though they may be perfectly comfortable taking them by another route.
This may be because of its common use in inner cities and with lower-income
people.

Preparation of intravenous injection


A clandestine kit containing materials to inject illicit drugs.

The drug, usually in a powder or crystal form (though not always), is dissolved in
water, normally in a spoon. Users draw the required amount of water into a
syringe and squirt this over the drugs. The solution is then mixed and heated
from below if necessary. Heating is used mainly with heroin, (though not always,
depending on the type of heroin)[1] but is also used when pharmaceutical drugs
such morphine, OxyContin or Dilaudid are injected to better separate the drug
from the waxy filler; amphetamines lose potency when heated and cocaine HCl
(powdered cocaine) dissolves quite easily. Heroin prepared for the European
market is insoluble in water and usually requires the addition of an acidifier such
as citric acid or ascorbic acid (Vitamin C) powder to dissolve the drug. Due to the
dangers from using lemon juice or vinegar to acidify the solution, packets of
citric acid and Vitamin C powder are available at needle exchanges in Europe. In
the U.S., vinegar and lemon juice are used to shoot crack cocaine. The acids
break down the rock-like substance and form a liquid mixture. Once the drugs are
dissolved a small syringe, usually 0.5 or 1 cc, is used to draw the solution
through a filter, usually cotton from a cigarette filter or cotton swab (cotton bud).
The preferred injection site is the crook of the elbow (i.e., the Median Cephalic
vein), on the user's non-writing hand. Other users opt to use the Basilic vein;
While it may be easier to "hit", caution must be exercised as two nerves run
parallel to the vein increasing the chance of nerve damage, as well as the chance
of an arterial "nick".
Harm reduction

Note that it is quite common for an IV user to use a single needle repeatedly or
share with other users. It's also quite uncommon for a sterilizing agent to be
used.
Compare this legitimate injection kit obtained from a needle-exchange program to
the user-compiled one above.

Harm reduction is an approach to public health intended to be a progressive


alternative to an approach requiring complete abstinence from drug use. While it
does not condone the taking of illicit drugs, it does seek to reduce the harms
arising from their use, both for the person taking illicit drugs and the wider
community.

A prominent method for addressing the issue of disease transmission among


intravenous drug users are needle exchange programs, in which facilities are
available to exchange used injection equipment for safe sterile equipment, often
without a prescription or fee. Such establishments also tend to offer free
condoms to promote safe sex and reduce disease transmission. The idea is to
slow disease transmission and promote public health by reducing the practice of
sharing used needles.

Safer injection of illicit drugs

A philosophy of harm reduction promotes information and resources for IV drug


users. General guidelines on safer injecting of various substances intravenously
are typically based on the following steps:

The area for drug preparation should be cleaned with warm soapy water or an
alcohol swab to minimize the risk of bacterial infection.

The equipment required involves new syringes and needles, swabs, sterile water,
filter, tourniquet and a clean spoon or stericup. In order to minimize the chance of
bacteria or viruses entering the bloodstream, people are advised to wash their
hands with soap and warm water. However, as people do not always have access
to hot water and soap when they are injecting, the philosophy of harm reduction
seeks to find the most realistic option that people can take. Alcohol swabs are
commonly distributed with injecting equipment, and while they are less effective
than hand washing, their use is more effective than nothing. Any sharing of
injecting equipment, even tourniquets, is highly discouraged, due to the high
danger of transmitting bacteria and viruses via the equipment.

Sterile water is also recommended to prevent infection. Many needle and syringe
programs distribute vials or ampoules of USP sterile water for this reason. Where
sterile water is not obtainable, the harm reduction approach recommends tap
water boiled for five minutes, and then allowed to cool.

Once the water and substance are combined in the mixing vessel, heat is
sometimes applied to assist the mixing. Filtering is recommended by health
services, as the mix can consist of wax or other non-soluble materials which are
damaging to veins. Wheel filters are the most effective filters, however cotton
wool or tampons can be used, although to be more effective, several filtrations
should be undertaken.

Once the mix is drawn into the syringe, air bubbles should be removed by flicking
the barrel with the needle pointed upwards and pressing the plunger to expel the
bubbles that pool at the top. This is done to prevent injection of air into the
bloodstream.

A tourniquet can be used to assist vein access. The tourniquet should not be on
too tight, or left on for too long, as this causes the veins to swell and stretch.
When injecting, the needle's 'hole' should face upward and be eased into the vein
at a 45 degree angle. In order to prevent stress on the vein, the needle should be
pointing towards the heart.

The plunger should be pulled back slightly (colloquially known as ‘jacking back’)
to ensure the needle is in the vein. Blood should appear in the barrel of the
syringe if this is the case. This process is termed aspirating the needle or
registering. When accessing a vein with unobstructed blood flow a "flashback,"
or sudden flash of red blood inside the needle tip, may occur spontaneously
when the needle enters the vein. Because sudden appearance of blood in the
needle/syringe alone does not guarantee proper needle placement (flashbacks
can also occur when a needle passes through a vein completely, enters an artery
inadvertantly, or otherwise is extravasated), aspirating the plunger on the syringe
is still considered a requisite step.

The tourniquet should then be taken off and the plunger gently pushed. After
injection, a clean tissue or cotton wool should be pressed against the injection
site to prevent bleeding. Although many people use an alcohol swab for this
purpose it is discouraged by health services as the alcohol interferes with blood
clotting.

Dispose of injecting gear using a 'sharps bin' if supplied. Other rigid-walled


containers such as a bottle are recommended as a second best option.

Epidemiology

An estimated 16 million people world wide use intravenous drugs, 3 million of


these are believed to be HIV positive.

Alternatives to injection

The safest alternative is, of course, not to take illicit drugs. The majority of legal
systems around the world encourage this option. Harm reduction acknowledges
that some people in a society will not choose this option and should at least be
provided information on safer means of taking illicit drugs to minimize the
individual health risks and the spread of viruses such as HIV and hepatitis C to
the wider community.

Snorting or sniffing (insufflation or nasal ingestion) is usually safer than injection


in terms of the relative danger of transmission of blood-borne viruses. However,
the membranes in the nose are very delicate and can rupture when snorting so
users should have their own snorting equipment not shared with anyone else, to
prevent viral transmission. As with injection, a clean preparation surface is
required to prepare a drug for snorting. Nasal membranes can be seriously
damaged from regular snorting.

Drugs can also be smoked (e.g., tobbacco or marijuana alone or mixed with
heroin) or 'chased' (originating from 'chasing the dragon' - inhaling the vapors of
the heated drug). Smoking and chasing have negligible risk of bacterial or viral
transmission and the risk of overdose is lessened compared to injecting, but they
still retain much of the 'rush' of injecting as the effects of the drug occur very
rapidly. Chasing is a far safer way to use heroin than injecting, with the best
option being to use new aluminum foil, first passing a cigarette lighter flame over
both sides to help sterilize it.

Swallowing tends to be the safest and slowest method of ingesting drugs. It is


safer as the body has a much greater chance to filter out impurities. As the drug
comes on slower, the effect tends to last longer as well, making it a favorite
technique on the dance scene for speed and ecstasy. People rarely take heroin
orally, as it is converted to morphine in the stomach and its potency is reduced
by more than 65% in the process. However, it is well known that oral
bioavailability of opioids is heavily dependent on the substance, dose, and
patient in ways that are not yet understood.[6] Pills like benzodiazepines are best
swallowed as they have chalk or wax fillers in them. These fillers won't irritate the
stomach, but pose serious health risk for veins or nasal membranes.

Shebanging involves spraying the dissolved drug into the nose to be absorbed
by the nasal membrane.

Shafting, or rectal ingestion, relies on the many veins in the anal passage passing
the drug into the blood stream quite rapidly. Some users find that trading off
some of the 'rush' for fewer health risks is a good compromise. Shafting usually
involves about 1.5 ml of fluid mixed with the drug.

Women have the added option of shelving, where drugs can be inserted in the
vagina. This is similar to the rectum, in that there are many blood vessels behind
a very thin wall of cells, so the drug passes into the bloodstream very quickly.
Care should be taken with drugs such as amphetamine that may irritate the
sensitive lining of the rectum and vagina.

Catheter
In medicine a catheter is a tube that can be inserted into a body cavity, duct or
vessel. Catheters thereby allow drainage, injection of fluids or access by surgical
instruments. The process of inserting a catheter is catheterization. In most uses a
catheter is a thin, flexible tube ("soft" catheter), although in some uses it is a
larger, solid tube ("hard" catheter). A catheter left inside the body, either
temporarily or permanently, may be referred to as an indwelling catheter. A
permanently inserted catheter may be referred to as a permcath.

The ancient Syrians created catheters from reeds. "Katheter" originally referred
to an instrument that was inserted such as a plug. The word "katheter" in turn
came from "kathiemai" meaning "to sound" with a probe. The ancient Greeks
inserted a hollow metal tube through the urethra into the bladder to empty it and
the tube came to be known as a "katheter".
Contents

* 1 Uses
* 2 Inventors
* 3 Materials
* 4 Interventional procedures
* 5 References
* 6 See also
* 7 External links

Uses

Placement of a catheter into a particular part of the body may allow:

* draining urine from the urinary bladder as in urinary catheterization, e.g., the
Foley catheter or even when the urethra is damaged as in suprapubic
catheterisation.
* drainage of urine from the kidney by percutaneous nephrostomy[1]
* drainage of fluid collections, e.g. an abdominal abscess
* administration of intravenous fluids, medication or parenteral nutrition with a
peripheral venous catheter
* angioplasty, angiography, balloon septostomy, balloon sinuplasty, catheter
ablation. Often the Seldinger technique is used.
* direct measurement of blood pressure in an artery or vein
* direct measurement of intracranial pressure
* administration of anaesthetic medication into the epidural space, the
subarachnoid space, or around a major nerve bundle such as the brachial plexus
* subcutaneous administration of insulin or other medications, with the use of
an infusion set and insulin pump
* A central venous catheter is a conduit for giving drugs or fluids into a large-
bore catheter positioned either in a vein near the heart or just inside the atrium.
* A Swan-Ganz catheter is a special type of catheter placed into the pulmonary
artery for measuring pressures in the heart.
* A Touhy borst adapter is a medical device used for attaching catheters to
various other devices.
* A Quinton catheter is a double or triple lumen, external catheter used for
hemodialysis.

Inventors

The modern application of the catheter was in use at least by 1868 when Dr.
N.B.Sornborger patented the Syringe and Catheter (patent #73402) with features
for fastening it to the body and controlling the depth of insertion.
David S. Sheridan was the inventor of the modern disposable catheter in the
1940s. In his lifetime he started and sold four catheter companies and was
dubbed the "Catheter King" by Forbes Magazine in 1988. He is also credited with
the invention of the modern "disposable" plastic endotracheal tube now used
routinely in surgery. Prior to his invention, red rubber tubes were used, sterilized,
and then re-used which often led to the spread of disease and also held a high
risk of infection. As a result Mr Sheridan is credited with saving thousands of
lives.

In the early 1900s, a Dubliner named Walsh and a famous Scottish urinologist
called Norman Gibbon teamed together to create the standard catheter used in
hospitals today. Named after the two creators, it was called the Gibbon-Walsh
catheter.

The Gibbon catheter and the Walsh catheter have been described and their
advantages over other catheters shown. The Walsh catheter is particularly useful
after prostatectomy for it drains the bladder without infection or clot retention.
The Gibbon catheter has largely removed the necessity of emergency
prostatectomy. It is also very useful in cases of urethral fistula. A simple
procedure such as dilatation of the urethra and passage of a Gibbon catheter
often causes the fistula to close. This catheter is also of use in the treatment of
urethral stricture and, as a temporary measure, in the treatment of retention of
urine caused by carcinoma of the prostate

Benjamin Franklin invented a flexible Catheter for his brother who had a bladder
stone.

Materials

A range of polymers are used for the construction of catheters, including silicone
rubber latex and thermoplastic elastomers. Silicone is one of the most common
choices because it is inert and unreactive to body fluids and a range of medical
fluids with which it might come into contact. On the other hand, the polymer is
weak mechanically, and a number of serious fractures have occurred in
catheters. It is widely used, for example, in breast implants where failures by
rupturing of the silicone shell are well attested. It is also used in Foley catheters
where fractures have been reported, often requiring surgery to remove the tip left
in the bladder.

List of medical inhalants


Contents
* 1 Drugs and therapeutic agents administered by inhalation
o 1.1 Anaesthetics
o 1.2 Anti-Asthmatics/Bronchodilators
o 1.3 Anti-Hypertensives
o 1.4 Antimicrobials
o 1.5 Pulmonary surfactants
o 1.6 Miscellaneous

Drugs and therapeutic agents administered by inhalation

Anaesthetics

* Desflurane
* Enflurane
* Ether
* Halothane
* Isoflurane
* Methoxyflurane
* Nitrous oxide
* Sevoflurane

Anti-Asthmatics/Bronchodilators

* Albuterol
* Arformoterol
* Beclomethasone
* Bitolterol
* Budesonide
* Budesonide/Formoterol
* Ciclesonide
* Cromolyn
* Dexamethasone
* Epinephrine
* Flunisolide
* Fluticasone
* Fluticasone/Salmeterol
* Formoterol
* Ipratropium
* Ipratropium/Albuterol
* Isoetharine
* Isoproterenol
* Levalbuterol
* Metaproterenol
* Mometasone
* Nedocromil
* Nitric oxide
* Pirbuterol
* Procaterol
* Racepinephrine (racemic epinephrine)
* Salmeterol
* Terbutaline
* Tiotropium
* Triamcinolone

Anti-Hypertensives

* Amyl nitrite
* Iloprost

Antimicrobials

* Pentamidine
* Ribavirin
* Tobramycin
* Zanamivir

Pulmonary surfactants

* Beractant
* Calfactant
* Colfosceril
* Exosurf
* Poractant

Miscellaneous

* Aromatic ammonia
* Dornase alfa
* Heliox
* Insulin
* Methacholine
* Nicotine
* Sodium chloride

Collected
By Gankidi
Raghavender
ZSMU

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