Download Introduction To Pharmacology

Introduction To Pharmacology
Dr. Hayder B Sahib
Ph. D., M.Sc., D.Sc. B.Sc. Pharm.
OBJECTIVES
• Describe how the size, shape and chemical nature of a
drug affects its pharmacodynamic and pharmacokinetic
properties.
• Compare and contrast the common routes of drug
administration.
• • Name and define the two major processes that allow a
drug to travel from its site of administration to its site of
action.
• • Explain why a hydrophobic drug is more likely than a
hydrophilic drug to rely upon metabolism for elimination.
GENERAL DEFINITIONS
• A. Pharmacology is the study of the interaction of
chemicals with living systems.
• B. Drugs are chemicals that act on living systems at the
chemical (molecular) level.
• C. Medical pharmacology is the study of drugs used for
the diagnosis, prevention, and treatment of disease.
• D. Toxicology is the study of the unpleasant effects of
chemical agents on living systems. It is usually
considered an area of pharmacology.
• E. Pharmacodynamic properties of a drug describe the action of the
drug on the body, including receptor interactions, dose-response
phenomena, and mechanisms of therapeutic and toxic action.
• F. Pharmacokinetic properties describe the action of the body on the
drug, including absorption, distribution, metabolism, and excretion.
• Elimination of a drug may be achieved by metabolism or by
excretion
• Placebo
a. A substance containing no medication and prescribed to reinforce a
patient's expectation to get well.
b. An inactive substance or preparation used as a control in an
experiment or test to determine the effectiveness of a medicinal drug.
• *Drug receptors:-The molecular components of the body
with which a drug interact to bring about its action.
• *Source and nature of the drugs
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1-Synthetic drugs :e.g. aspirin, paracetamol, antidiabetics.
2-Natural drugs:
a-Plant source: e.g. morphine, quinine.
b-Animal source; e.g. heparin, gonadotrophins.
c-Micro-organisms: e.g. penicillin, streptomycin.
d-Minerals: e.g. Fe, Mg.
3-Semi-synthetic drugs: e.g. ampicillin, amoxicillin.
4-Bio-synthetic drugs: e.g insulin ( by inserting the human
pro-insulin gene in E.coli).
• *Drug nomenclature:• Typically a drug has:• 1-one or more proprietary (brand) names e.g
Amoxil, Novamoxil
• 2-a non-proprietary (generic)name e.g
Amoxacillin
• 3-pre-market manufactures code e.g BRL-2333
• 4-chemical name e.g 6-amino(4hydroxyphenyl)acetyl amino 2-carboxylic acid.
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The non-proprietary name is worth to be remembered because it provide:1-Clarity:because it gives information of the class of the drug
2-Economy:usually cheaper than proprietary drug
3-Convenience:pharmacists supply whatever version they stock.
• Drug Evaluation:-Includes;
• 1-Pre clinical( animal) tests
• 2-Clinical (human ) tests.
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1-Pre-clinical tests: includes:
a-Pharmacological profile test:
Description of all the pharmacological effects of a drugs
(effects
on BP, GIT, respiration, renal function, endocrine function, and CNS )
b-Reproductive toxicity test:
Involves the study of the fertility effects of the drug and
teratogenic and mutagenic effects.
its
• Teratogenesis: Induction of developmental defects in the
somatic tissue of the fetus
• Mutogenesis: Induction of changes in the genetic
material of the animals of any age and therefore induction of
heritable abnormalities
• Carcinogenesis: Is the induction of malignant characteristic in
cells.
• c-Pharmacokinetic testing:
• Including studies on absorption, metabolism, distribution and
elimination of the drug on laboratory animals.
• d-Chemical and pharmaceutical development
• to study drug synthesis, purification, and stability.
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• 2-Clinical test( clinical trial )
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*Phase 1 (human pharmacology):
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-Healthy volunteers (20-50 subjects) to study:
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-Pharmacokinetic (absorption, distribution,
metabolism excretion)
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-Pharmacodynamics (biological effects)
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-Tolerability ,
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-Safety ,
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- Efficacy
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*Phase 2 ( therapeutic exploration)
-Patients (50-300 )
-Pharmacokinetic and Pharmacodynamic , dose
ranging in
carefully controlled
studies for efficacy and safety which
may
involve comparison with placebo.
• *Phase 3( therapeutic confirmation)
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-Patients(250-1000+)
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-Randomized controlled trials.
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-Efficacy on a substantial scale, safety,
comparison with existing drugs.
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*Phase 4 (therapeutic use) (post-licensing
study)
-Patients(2000-10000+)
-Surveillance for safety and efficacy
-Further formal therapeutic trials.(comparison
with other
drugs
-Marketing and pharmacoeconomic studies
THE NATURE OF DRUGS
• A. Size. The great majority of drugs lie in the range from
molecular weight 100 to 1,000. Drugs in this range are large
enough to allow selectivity of action and small enough to
allow adequate movement within the various
compartments in the body.
• B. Chemistry and reactivity. Drugs may be small, simple
molecules (amino acids, simple amines, organic acids,
alcohols, esters, ions, etc.), carbohydrates, lipids, or even
proteins.
• Binding of drugs to their receptors
the specific molecules in a biologic system that mediate
drug effects, is usually by noncovalent bonds (hydrogen
bonds, van de Waals attractions, and ionic bonds)
• less commonly by covalent bonds.
• Weaker, non-covalent bonds require a better fit of the
drug to the receptor binding site and, usually, a
reversible type of action.
• Very strong bonding, eg, covalent bonds, usually involves
less selectivity and an irreversible interaction.
• Shape. The overall shape of a drug molecule is important
for the fit of the drug to its receptor.
• Between a quarter and a half of all drugs in use exist as
stereoisomers. In most cases the stereoisomers are chiral
enantiomers. Enantiomers are mirrored image twin
molecules that result from the presence of an
asymmetric carbon, or in a few cases, other asymmetric
atoms in their structures.
• Chiral enantiomers often differ in their ability to bind to
and alter the function of receptors.
• They also can differ in their rates of elimination and in
their toxicity. Most chiral drugs are still provided
• Drug passage across cell membranes.
• Is determined by the natural processes of the fallowing;
• 1- Passive diffusion.
• 2- Filtration.
• 3- Carrier-mediated transport.
• 1- Passive diffusion.
• It refers simply to the natural tendency of any substances
to move passively from an area of high concentration to
one of low concentration.
• This process characterized by:• -cellular energy is not required
• -process does not become saturated.
• -it is not inhibited by other substances.
Effect of Ph on drug absorption:
The extent to which drugs are soluble in water or lipid is
central to their capacity to cross cell membrane.
Water or lipid solubility is influenced by environmental
pH and the structural properties of the molecule.
It is useful to classify drugs in physicochemical sense
into:
A- variably ionized according to environmental Ph.
B-incapable of becoming ionized whatever the
environm.Ph.
C-permanently ionized whatever the environmental Ph.
A-variably ionized according to environmental Ph.
*Many drugs are weak electrolytes i.e. their structural
groups ionize according to environmental Ph.
The degree of ionization influences lipid solubility and hence
diffusibility .
*The degree to which molecule has tendency to ionize is
given by dissociation constant (pKa).
If the pKa of the drug and the pH Of the environment are
known , the fraction of molecules in ionized form can be
predicted
• *In an acid environment, an acidic
group(drug) tends to retained a H ion and
remains unionized , while in basic
environment it will loss H ion and become
ionized .
• The opposite is the case for a basic
group(drug).
• - In general:• Acidic drugs become less ionized in acidic environment
and basic drug becomes less ionized in a basic (alkaline)
environment so it is:
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- more unionized
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-more lipid-soluble (well absorbed)
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-more diffusible
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• *Acidic drug becomes more ionized in basic
environment and basic drug becomes more ionized
in acidic environment so it is:
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-more ionized
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-less lipid soluble (not absorbed)
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-less diffusible
• Ion-trapping phenomenon:• At steady state- an acidic drug would accumulate on
the more basic side of a membrane and a basic drug
on the more acidic side.
• Clinical significance of ion trapping:• *Basic drugs taken by mother can accumulate in the fetal
circulation and breast milk and can have harmful effects
in the fetus and breast-milk fed baby.
• *Acidification or alkalization of urine can accelerate the
excretion of basic or acidic drugs that have reached toxic
concentration in the body. Examples:
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-To increase excretion of acidic drugs such as
Phenobarbital and salicylate, I.V bicarbonate is given.
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-To increase excretion of basic drugs such as
amphetamine, ammonium chloride may be given.
• B-Drugs incapable of becoming ionized:
• These include digoxin and steroid hormones . They
are always unionized (nonpolar) and they are
unaffected by environmental pH
• C-Permanently ionized drugs:
• These drugs are always ionized and not absorbed
orally(not cross membranes) and not given orally e.g.
heparine, tubocurarine.
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• 2- Filtration:
• Aqueous channels in the tight junction between
epithelial cells allow the passage of some watersoluble substances (low mol. weight e.g. ethanol)
• Filtration play minor role in drug transfer in the body
except in glomerular filtration.
• 3-Carrier-mediated transport:
• Some drugs cross cell membrane against a
concentration gradient i.e. by active transport
and this process characterized by:
• -involve endogenous molecules.
• -expend cellular energy.
• -highly specific.
• -subjected to saturation
• -can be inhibited.
• Examples:
• -absorption of iron by gut.
• -levadopa cross blood-brain Barrier.
• The order of reaction or process:
• 1-First-order kinetic (process)
• * The rate at which absorption, distribution,
metabolism and excretion of drug occur are
directly proportional to its concentration in the
body (high at high concentration and low at low
concentration ).
• *In other word, a constant fraction of drug
is(absorbed, distributed, metabolized and excreted)
per-unit of time.
• *Most drug are subjected to first-order kinetic.
• *Blood concentration declines in linear fashion over
time.
• *In 1st order kinetic , half-life is constant regardless
the amount of drug in the body.
• 2-Zero-order kinetic (process)(saturation kinetic)
• *The rate of process reaches maximum amount at which
it stay constant, e.g. due to limited activity of an enzyme,
and further increase in rate is impossible despite an
increase in the dose.
• *The metabolic process for most drugs will show zeroorder kinetic only at very high concentration.
• *The metabolic capacity for few drugs become saturated
at concentration within therapeutic range (e.g. phenytoin,
aspirin, carbamazepin, ethanol.)
• *Passive diffusion does not show zero-order kinetic.