This document provides an overview of the history and principles of pharmacology. It discusses: - How early pharmacology focused on crude plant extracts and their effects were not well understood. Identification of active compounds like morphine revolutionized the field. - Advances in the 18th/19th centuries through animal experiments and establishment of pharmacology as a science. Key figures like Schmiedeberg established fundamental concepts. - 20th century breakthroughs in synthesis of new drugs and understanding of drug mechanisms of action through discovery of targets like receptors. This allowed rational design of highly effective therapies. - Modern pharmacology principles including a drug's size, shape, reactivity and how these influence receptor binding and

1. General principles of pharmacology
PRESENTOR: DR.C.RAJALAKSHMY @ ARTHI,
PG – II year
DEPARTMENT OF ANAESTHESIA

2.  For thousands of years most drugs were crude natural products of unknown
composition and limited efficacy.
1. Plant extracts -Symptom-based empiric approach.
 Concerned exclusively with understanding the effects of natural substances,
mainly plant extracts – and a few (mainly toxic) chemicals such as mercury and
arsenic.
 Friedrich Sertürner, a young German, purified morphine from opium in 1805.
 Other substances quickly followed, even their structures were unknown, these
compounds showed that chemicals, not magic or vital forces, were responsible
for the effects that plant extracts produced on living organisms.
 Early pharmacologists focused most of their attention on such plant derived
drugs as quinine, digitalis, atropine, ephedrine, strychnine and others.

3. 2. Animal experiments, primarily aimed at understanding physiological processes,
were started in the 18th century.
 These were pioneered by F. Magendie and Claude Bernard, who also adapted
them to study effects of certain drugs.
 Pharmacology as an experimental science was ushered by Rudolf Buuchheim
who founded the first institute of pharmacology in 1847 in Germany.
 The first use of a structural formula to describe a chemical compound was in
1868.
 In the later part of the 19th century, Oswald Schmiedeberg, regarded as the
'father of pharmacology', together with his many disciples propounded some of
the fundamental concepts in pharmacology.
 Since then drugs have been purified, chemically characterized and a vast variety
of highly potent and selective new drugs have been developed.

4. 3. In 20th century - Identification of compounds targeting more fundamental
biologic processes.
 In the beginning, the fresh wind of synthetic chemistry began to revolutionise
the pharmaceutical industry, and with it the science of pharmacology.
 New synthetic drugs, such as barbiturates and local anaesthetics, began to
appear, and the era of antimicrobial chemotherapy began with the discovery
by Paul Ehrlich in 1909 of arsenical compounds for treating syphilis.
 Further breakthroughs came when the sulfonamides, the first antibacterial
drugs, were discovered by Gerhard Domagk in 1935, and with the
development of penicillin by Chain and Florey during the Second World War,
based on the earlier work of Fleming.
 These few well-known examples show the growth of synthetic chemistry, and
the resurgence of natural product chemistry, caused a dramatic revitalisation
of therapeutics in the first half of the 20th century.

5. 4. Understanding basic biologic processes will lead to highly effective new
therapies -The term “magic bullet,” coined by Paul Ehrlich to describe the
search for effective compounds for syphilis, captures the essence of the hope.
5. Modern drug development - Structural modifications to develop compounds
with specificity for the chosen target, lack of “off-target” effects, and
pharmacokinetic properties suitable for human use –
 The mechanism of action including molecular target of many drugs has
been elucidated.
 This has been possible due to prolific growth of pharmacology which forms
the backbone of rational therapeutics.

6. • The science of drugs (Greek: Pharmacon-drug; logos-
discourse in).
• It deals with interaction of exogenously administered
chemical molecules with living systems
Pharmacology
• A chemical substance of known structure, other than a
nutrient or an essential dietary ingredient, which, when
administered to a living organism, produces a biological
effect
• May be synthetic chemicals, chemicals obtained from plants
or animals, or products of genetic engineering
Drug
The WHO ( 1966) has given a more comprehensive definition-
"Drug is any substance or product that is used or is intended to be used to modify or
explore physiological systems or pathological states for the benefit of the recipient."

7. • It is the art and science of compounding and dispensing drugs or
preparing suitable dosage forms for administration of drugs to man or
animals.
• Includes collection, identification, purification, isolation, synthesis,
standardization and quality control of medicinal substances.
• The large scale manufacture of drugs is called Pharmaceutics, which is
primarily a technological science.
Pharmacy
• Chemical preparation, which usually, but not
necessarily, contains one or more drugs, administered
with the intention of producing a therapeutic effect.
• Usually contain other substances (excipients,
stabilisers, solvents, etc.) besides the active drug, to
make them more convenient to use.
Medicine

9. • It is the scientific study of drugs (both old and new) in
man .
• It includes pharmacodynamic and pharmacokinetic
investigation in healthy volunteers as well as in patients.
• Evaluation of efficacy and safety of drugs and
comparative trials with other forms of treatment;
surveillance of patterns of drug use, adverse effects, etc.
are also part of it.
• The aim is to generate data for optimum use of drugs and
the practice of 'evidence based medicine'.
Clinical
pharmacology

10. THE NATURE OF DRUGS:
 The drug molecule interacts as an agonist (activator) or antagonist (inhibitor)
with a specific target molecule that plays a regulatory role in the biologic system.
This target molecule is called a receptor.
 Drugs known as chemical antagonists may interact directly with other drugs,
 A few drugs (osmotic agents) interact almost exclusively with water molecules.
 Drugs may be synthesized within the body (eg, hormones) or may be chemicals
not synthesized in the body (ie, xenobiotics).
 Poisons are drugs that have almost exclusively harmful effects. However,
Paracelsus (1493–1541) famously stated that “the dose makes the poison,”
meaning that any substance can be harmful if taken in the wrong dosage.
 Toxins are usually defined as poisons of biologic origin, ie, synthesized by plants
or animals, in contrast to inorganic poisons such as lead and arsenic.

11. THE PHYSICAL NATURE OF DRUGS
 To interact chemically with its receptor, a drug molecule must have the appropriate size,
electrical charge, shape, and atomic composition.
 A drug is often administered at a location distant from its intended site of action,
Therefore, a useful drug must have the necessary properties to be transported from its
site of administration to its site of action.
 Finally, a practical drug should be inactivated or excreted from the body at a reasonable
rate so that its actions will be of appropriate duration.
 Drugs may be solid at room temperature (eg, aspirin, atropine), liquid (eg, nicotine,
ethanol), or gaseous (eg, nitrous oxide). These factors often determine the best route of
administration.
 A number of useful or dangerous drugs are inorganic elements, eg, lithium, iron, and
heavy metals.
 Many organic drugs are weak acids or bases. This has important implications for the way
they are handled by the body, because pH differences in the various compartments of the
body may alter the degree of ionization of weak acids and bases.

12. DRUG SIZE:
 The molecular size of drugs varies from very small (lithium ion, molecular weight [MW]
7) to very large (eg, alteplase [t-PA], a protein of MW 59,050). However, most drugs have
molecular weights between 100 and 1000.
 The lower limit of this narrow range is probably set by the requirements for specificity of
action.
To have a good “fit” to only one type of receptor, a drug molecule must be sufficiently
unique in shape, charge, and other properties to prevent its binding to other receptors. To
achieve such selective binding, it appears that a molecule should in most cases be at least
100 MW units in size.
 The upper limit is determined primarily by the requirement that drugs must be able to
move within the body (eg, from the site of administration to the site of action).
Drugs much larger than MW 1000 do not diffuse readily between compartments of the
body. Therefore, very large drugs (usually proteins) must often be administered directly into
the compartment where they have their effect.
 In the case of alteplase, a clot-dissolving enzyme, the drug is administered directly into
the vascular compartment by intravenous or intra-arterial infusion.

13. DRUG REACTIVITY & DRUG-RECEPTOR BONDS:
 Drugs interact with receptors by means of chemical forces or bonds.
 These are of three major types: covalent, electrostatic, and hydrophobic.
 Covalent bonds are very strong and in many cases not reversible under biologic
conditions.
Thus, the covalent bond formed between the acetyl group of acetylsalicylic acid (aspirin)
and cyclooxygenase, its enzyme target in platelets, is not readily broken. The platelet
aggregation–blocking effect of aspirin lasts long after free acetylsalicylic acid has
disappeared from the bloodstream (about 15 minutes) and is reversed only by the
synthesis of new enzyme in new platelets, a process that takes several days.
 Electrostatic bonding is much more common than covalent bonding in drug-receptor
interactions.
They vary from relatively strong linkages between permanently charged ionic molecules
to weaker hydrogen bonds and very weak induced dipole interactions such as van der
Waals forces and similar phenomena.
 Electrostatic bonds are weaker than covalent bonds.

14.  Hydrophobic bonds are usually quite weak and are probably important in the
interactions of highly lipid-soluble drugs with the lipids of cell membranes
and perhaps in the interaction of drugs with the internal walls of receptor
“pockets.”
 The specific nature of a particular drug-receptor bond is of less practical
importance than the fact that drugs that bind through weak bonds to their
receptors are generally more selective than drugs that bind by means of very
strong bonds.
This is because weak bonds require a very precise fit of the drug to its receptor if
an interaction is to occur.
Only a few receptor types are likely to provide such a precise fit for a particular
drug structure. Thus, if we wished to design a highly selective short-acting drug
for a particular receptor, we would avoid highly reactive molecules that form
covalent bonds and instead choose a molecule that forms weaker bonds.
 A few substances that are almost completely inert in the chemical sense
nevertheless have significant pharmacologic effects. For example, xenon, an
“inert” gas, has anesthetic effects at elevated pressures.

15. DRUG SHAPE:
 The shape of a drug molecule must be such as to permit binding
to its receptor site via the bonds just described.
 Optimally, the drug’s shape is complementary to that of the
receptor site in the same way that a key is complementary to a
lock.
 Furthermore, the phenomenon of chirality (stereoisomerism) is so
common that more than half of all useful drugs are chiral
molecules; that is, they can exist as enantiomeric pairs.
Drugs with two asymmetric centers have four diastereomers, eg,
ephedrine, a sympathomimetic drug.

16.  In most cases, one of these enantiomers is much more potent than its mirror
image enantiomer, reflecting a better fit to the receptor molecule.
 If one imagines the receptor site to be like a glove into which the drug
molecule must fit to bring about its effect, it is clear why a “left-oriented” drug
is more effective in binding to a left-hand receptor than its “right-oriented”
enantiomer.
 The more active enantiomer at one type of receptor site may not be more
active at another receptor type, eg, a type that may be responsible for some
other effect.
 For example, carvedilol, a drug that interacts with adrenoceptors, has a single
chiral center and thus two enantiomers . One of these enantiomers, the (S)(–)
isomer, is a potent β-receptor blocker. The (R)(+) isomer is 100-fold weaker at
the β receptor. However, the isomers are approximately equipotent as α-
receptor blockers.
 Ketamine is an intravenous anesthetic. The (+) enantiomer is a more potent
anesthetic and is less toxic than the (–) enantiomer. Unfortunately, the drug is
still used as the racemic mixture.

17.  Finally, because enzymes are usually stereoselective, one drug
enantiomer is often more susceptible than the other to drug
metabolizing enzymes.
 As a result, the duration of action of one enantiomer may be quite
different from that of the other.
 Similarly, drug transporters may be stereoselective.
 But most studies of clinical efficacy and drug elimination in
humans have been carried out with racemic mixtures of drugs
rather than with the separate enantiomers.
 At present, only a small percentage of the chiral drugs used
clinically are marketed as the active isomer—the rest are available
only as racemic mixtures.
 As a result, most patients receive drug doses of which 50% is less
active or inactive.
 Some drugs are currently available in both the racemic and the
pure, active isomer forms.

18. Rational Drug Design:
 Implies the ability to predict the appropriate molecular
structure of a drug on the basis of information about its
biologic receptor.
 Until recently, no receptor was known in sufficient detail to
permit such drug design.
 Instead, drugs were developed through random testing of
chemicals or modification of drugs already known to have
some effect.
 A few drugs now in use were developed through molecular
design based on knowledge of the three dimensional structure
of the receptor site.
 Computer programs are now available that can optimize drug
structures to fit known receptors. As more becomes known
about receptor structure, rational drug design will become
more common.

19. INDICATIONS FOR DRUG THERAPY: RISK VERSUS BENEFIT
• It is self-evident that the benefits of drug therapy should outweigh the risks.
• Benefits fall into two broad categories:
 Those designed to alleviate a symptom and
 Those designed to prolong useful life.
• An increasing emphasis on the principles of evidence-based medicine and techniques
such as large clinical trials and meta-analyses have defined benefits of drug therapy .
• An increasing body of evidence supports the idea, that individual patients may display
responses that are not expected from large population studies and often have
comorbidities that typically exclude them from large clinical trials.
• In addition, therapies that provide symptomatic benefits but shorten life may be
entertained in patients with serious and highly symptomatic diseases such as heart
failure or cancer. These considerations illustrate the continuing, highly personal
nature of the relationship between the prescriber and the patient.

20. Adverse Effects:
• Some are so common and so readily associated with drug therapy that they
are identified very early during clinical use of a drug.
• By contrast, serious adverse effects may be sufficiently uncommon that they
escape detection for many years after a drug begins to be widely used.
• To identify serious adverse effects, potential approaches range from an
increased understanding of the molecular and genetic basis of variability in
drug actions to expanded post-marketing surveillance mechanisms.
• None of these have been completely effective, so practitioners must be
continuously vigilant to the possibility that unusual symptoms may be related
to specific drugs, or combinations of drugs, that their patients receive.

21. • Pharmacogenetics - Unusual drug responses, segregating in families
• Pharmacogenomics- This term overlaps with pharmacogenetics, describing the
use of genetic information to guide the choice of drug therapy on an individual
basis.
 The underlying principle is that differences between individuals in their
response to therapeutic drugs can be predicted from their genetic make-up
which may hold the opportunity of allowing practitioners to prescribe
personalized, highly effective, and safe therapies.

22. Therapeutic Index: Beneficial and adverse reactions to drug therapy can be
described by a series of dose-response relations.
• Well tolerated drugs demonstrate a wide margin, termed the therapeutic ratio,
therapeutic index, or therapeutic window, between the doses required to
produce a therapeutic effect and those producing toxicity.
• Monitoring plasma concentrations can be a highly effective aid in managing
drug therapy by enabling concentrations to be maintained above the minimum
required to produce an effect and below the concentration range likely to
produce toxicity.
• Such monitoring has been widely used to guide therapy with specific agents,
such as certain antiarrhythmics, anticonvulsants, and antibiotics.

24. The Conduct of Clinical Trials:
• Clinical trials of drugs are designed to acquire information about the
pharmacokinetic and pharmacodynamic properties of a candidate drug in
humans.
• Efficacy must be proven and an adequate margin of safety established for a
drug to be approved for sale.
• The FDA-regulated clinical trials typically are conducted in four phases.
Phases I-III are designed to establish safety and efficacy,
Phase IV postmarketing trials delineate additional information regarding new
indications, risks, and optimal doses and schedules.

26. • The chain of events between administration of a drug and production of these
effects in the body can be divided into two components, both of which contribute to
variability in drug actions.
• The first component comprises the processes that determine drug delivery to, and
removal from, molecular targets. The resulting description of the relationship
between drug concentration and time is termed pharmacokinetics.
• The second component of variability in drug action comprises the processes that
determine variability in drug actions despite equivalent drug delivery to effector
drug sites. This description of the relationship between drug concentration and
effect is termed pharmacodynamics.

28. THANK YOU

29. References:
1. RANG AND DALE’S Pharmacology, 8 th edition.
2. Basic & Clinical Pharmacology Edited by Bertram G. Katzung, MD, PhD
Professor Emeritus Department of Cellular & Molecular Pharmacology
University of California, San Francisco Fourteenth Edition.
3. Goodman and Gilman's The Pharmacological Basis of Therapeutics, 13th
Edition