PHARMACOLOGY TRANS 1

Section I: Basic Principles

o Insertion of appropriate “healthy” gene into

OUTLINE somatic cells

1. Introduction Homozygous knockout

2. Drug Receptor & Pharmacodynamics • Have complete suppression of breeding
3. Pharmacokinetics & Pharmacodynamics: Rational Dosing Heterozygous knockout
& The Time Course of Drug Action • Have partial suppression of breeding
4. Drug Biotransformation Some patients has greater response to drugs than other because of a
5. Developmental Regulation of Drugs VERY SMALL GENETIC MODIFICATION that results in DECREASED
ACTIVITY OF AN ENZYME responsible for eliminating drugs.
General Principles of Pharmacology
Introduction I. Nature of Drugs
Pharmacology
• Study of substances that interact with living systems through Agonist - Activator
chemical processes Antagonist - Inhibitor
o Medical Pharmacology Receptor – Target molecule
▪ Science of substances used to prevent, Chemical Antagonist
diagnose, and treat disease • Interacts directly with other drugs
o Toxicology Osmotic agents
▪ Branch of pharmacology that deals with • Interacts EXCLUSIVELY WITH WATER MOLECULES
undesirable effects of chemicals on Hormones
living systems • Drugs may be synthesized within the body
History of Pharmacology Xenobiotics
Materia Medica • Drugs not synthesized within the body
• Science of drug preparation and medical use of drugs Poisons
• Precursor of pharmacology • Drugs that have almost exclusively harmful effects
Francois Magendie & Claude Bernard Toxins
• Developed the methods of experimental physiology and • Defined as poisons of biologic origin
pharmacology in the late 18th and early 19th centuries “The dose makes the poison” – Paracelsus, 1493-1531
Pharmacogenomics Useful Drugs Properties:
• Relation of individual’s genetic makeup to his/her response 1. Appropriate size
to specific drugs 2. Electrical charge
o siRNAs & miRNAs 3. Shape
▪ Therapeutic agents 4. Atomic composition
o ANOs 5. Administered at a local distant from its intended site of
▪ Complementary to natural RNA or DNA action
▪ Interfere with the readout of genes and 6. Should be inactivated/excreted
the transcription of RNA
TWO GENERAL PRINCIPLES TO REMEMBER: Physical Nature of Drugs
1. All substances are toxic under certain circumstances and the Example of Drugs At Room Temperature
chemicals in botanicals are no different from the ones Aspirin Solid*
manufactured. Atropine
2. All dietary supplements and all therapies promotes as Nicotine Liquid*
health-enhancing should meet the same standards of Ethanol
efficacy and safety as conventional drugs and medical Nitrous oxide Gaseous*
therapies. *These factors determine the best route of administration
o NO SEPARATION BETWEEN SCIENTIFIC MEDICINE *Inorganic – useful/dangerous
AND ALTERNATIVE/COMPLEMENTARY MEDICINE *Organic – weak acids/bases
Pharmacology & the Pharmaceutical Industry
A truly new drug requires the discovery of a new target Drug size
Target – the pathophysiologic process or substrate of a disease
• Molecular size of drugs varies from very small (lithium ion,
Pharmacology & Genetics
MW 7) to very large (alteplase, MW 59,050).
Diseases are inherited because there is a heritable abnormality in the
o Alteplase – administered intravenous/intra-
DNA
arterial infusion
• It can now be cured via gene therapy
• Common size – MW 100-1000

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PHARMACOLOGY : Section I : Basic Principles TRANS 1
o Lower limit for specificity of action; Upper limit for • Ex. Ketamine
drug to be able to move within the body o IV anesthetic
• To have good “fit” to ONLY ONE type of receptor, drug o + enantiomer more potent anesthetic than –
molecule must be unique in SHAPE, CHARGE, AND OTHER o Still used as racemic mixture
PROPERTIES. • <Racemic mixture drugs in market
• Selective binding – to be able to achieve this a molecule o 50% less active, inactive or actively toxic
should be at least 100 MW units in size

Drug Reactivity and Drug-Receptor Bonds Rational Drug Design

Three major types of chemical forces/bonds: It implies the ability to predict the appropriate molecular structure of
1. Covalent a drug on the basis of information about its biologic receptor.
a. Very strong No receptor was known to permit such drug design.
b. Not reversible under biologic conditions
c. Formed between the acetyl group of acetylsalicylic Receptor Nomenclature
acid (Aspirin) and cyclooxygenase are not readily ---
broken Drug-Body Interactions
i. Platelet aggregation-blocking effect of Pharmacodynamic
aspirin lasts long after free acetylsalicylic • Actions of the drug on the body
acid has disappeared from the • Determine the group in which the drug is classified
bloodstream (15 mins) • Play a major role in deciding whether that group is
d. DNA-alkylating agents used in cancer appropriate therapy for particular symptom or disease
chemotherapy to disrupt cell division in the tumor Pharmacokinetic
2. Electrostatic • Action of the body on the drug
a. More common than covalent • Absorption, distribution and elimination of drugs
b. Vary from relatively strong linkages between
permanently charged ionic molecules to weaker Pharmacodynamic Principles
hydrogen bonds and very weak induced dipole • Drug (D) + receptor-effector (R) → drug-receptor-effector
interactions complex → effect
c. Weaker than covalent bonds • D + R → drug-receptor complex → effector molecule →
3. Hydrophobic effect
a. Weak • D + R → D-R complex → activation of coupling molecule →
b. Important in: effector molecule → effect
i. The interactions of highly lipid-soluble • Inhibition of metabolism of endogenous activator →
drugs with the lipids of cell membrane increased activator action on an effector molecule →
ii. The interaction of drugs with the increased effect
internal walls of receptor “pockets” **Final change in function is done by an effector mechanism
**Drugs that bind through the weak bonds are more selective than
those that bind through strong bonds I. Types of Drug-Receptor Interactions
**Because weak bonds require very precise fit of the drug to the Agonist drugs
receptor
• Bind to and activate the receptor which
directly/indirectly brings about the effect
Drug Shape
• Some receptors incorporate effector machinery in the
Drug’s shape is complementary to that of the receptor site in the same
same molecule, so that drug binding brings about the
way that a key is complementary to the lock.
effect directly
Chirality (Stereoisomerism)
• Some are linked to a separate effector molecule.
• Drugs that appear as enantiomeric pairs
Pharmacologic antagonist drugs
• Ex. Ephedrine – Sympathomimetic drug
• By binding to a receptor, bind with and prevent
o 2 asymmetric centers
binding by other molecules.
o 4 diastereomers
• Ex. Acetylcholine receptor blockers (Atropine)
• Ex. Carvedilol
o They prevent access of acetylcholine to the
o Drug that interacts with adrenoceptors
receptor site
o Single chiral center
o Reduce the effects of acetylcholine
o 2 enantiomers
• Can become irreversible/pseudoirreversible and
▪ (S)(-) isomer
cannot be displaced by increasing agonist
• Potent B-receptor blocker
concentration
▪ (R)(+) isomer
Allosteric drugs
• 100-fold weaker at the B
• Bind to the same receptor molecule but do not
receptor
prevent binding of agonist
**Isomers are approx. equipotent as a-receptor
• May enhance or inhibit action of agonist molecule
blockers

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PHARMACOLOGY : Section I : Basic Principles TRANS 1
• Allosteric inhibition is not overcome by increasing the o Activated by the endogenous transmitter
dose of agonist GABA and causes inhibition of postsynaptic
cells
II. Agonists That Inhibit Their Binding Molecules • Cause anxiety and agitation
Drugs that mimic agonist drugs by inhibiting the molecules IV. Duration of Drug Action
responsible for terminating the action of an endogenous agonist Termination of drug action is a result of one of several
• Ex. Acetylcholinesterase inhibtors processes. In some cases, the effect lasts only as long
o Slowing the destruction of endogenous as the drug occupies the receptor, and dissociation of
acetylcholine drug from the receptor automatically terminates the
o Cause cholinomimetic effects that closely effect.
resemble the actions of cholinoceptor V. Receptors and Inert Binding Sites
agonist molecules eventho cholinesterase To function as a receptor:
inhibitors do not bind or only incidentally 1. An endogenous molecule must be selective in choosing
bind to cholinoceptors. ligands (drug molecules)
o More selective; Less toxic 2. It must change its function upon binding in such a way
III. Agonists, Partial Agonist, and Inverse Agonists that the function of the biologic system (cell, tissue, etc)
Constitutive activity is altered.
o In the absence of agonist, receptor pool Inert binding site
mused exist in the Ra form and produce • Nonregulatory molecule such as plasma albumin will result
same physiologic effect as agonist-induced in no detectable change in the function of the biologic
activity system
o Recognition is depends on the: • Not completely without significance, however, because it
▪ Receptor density affects the distribution of drug within the body and
▪ Concentration of coupling determines the amount of free drug in the circulation.
molecules Pharmacokinetic Principles
▪ Number of effectors in the system Prodrug – precursor chemical
Agonists Note: drugs should be able to reach its intended site after
• High affinity for the Ra configuration and stabilizes it, administration, only in some can it be directly applied such as topical
so that a large percentage of total pool resides in the drugs.
Ra-D fraction and a large effect is produced. Drug should be absorbed → distributed → permeating the barriers
Full Agonists → eliminated
• When administered at concentration sufficient to A. Permeation
saturate the receptor pool, can activate their receptor- a. Aqueous diffusion
effector system to the maximum extend of which the i. Occurs within large aqueous
system is capable compartments of the body and across
• Cause shift of almost all of the receptr pool to the Ra-D epithelial membrane tight junctions and
pool the endothelial lining of blood vessels
Partial Agonists ii. Permit passage of molecules with large
• Bind to the same receptors and activate them in the MW (20,000-30,000)
same way iii. Driven by concentration gradient of the
• But do not evoke great response permeating drug
• Do not stabilize the Ra configuration as fully as full b. Lipid diffusion
agonists i. Most important limiting factor of drug
• Has low intrinsic efficacy permeation because of large number of
o Independent of affinity for the receptor lipid barriers
• Ex. B-adrenoceptor partial agonist, ii. Lipid:aqueous partition coefficient
o Act either as an agonist or as an antagonist determines how the molecule moves
Neutral antagonism between aqueous and lipid media.
• Presence of the antagonist at the receptor site will c. Special carriers
block access of agonists to the receptor and pre- vent i. For those that are two large or two
the usual agonist effect insoluble in lipid
Inverse agonists ii. By active transport or facilitated
• Has stronger affinity for the Ri diffusion
d. Endocytosis and exocytosis
• Stabilizes a large fraction in the Ri-D pool
i. Endocytosis
• Reduce any constitutive activity, thus resulting in
1. Substance should be bound to
effects that are the opposite of the effects produced
a cell-surface receptor which is
by conventional agonists at that receptor.
then engulfed by cell
• Ex. Y-aminobutyric acid receptor effector
membrane and carried into
the cell

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PHARMACOLOGY : Section I : Basic Principles TRANS 1
2. Examples: “For I know the plans I have for you declares the Lord, “plans to
a. Transport of Vitamin prosper and not to harm you, plans to give you hope and a future”
B12 with IF Jeremiah 29:11
b. Iron with tansferrin
ii. Exocytosis
1. Secretion of substances from
cells
2. Example:
a. Neurotransmitter
substances stored in
membrane-bound
vesicles in nerve
endings
B. Fick’s Law of Diffusion
Passive flux of molecules down a concentration gradient

• C1 is the higher concentration

• C2 is the lower concentration
• Area is the cross-sectional area of the diffusion
path
• Permeability coefficient is a measure of the
mobility of the drug molecules in the medium of
the diffusion path
• Thickness is the thickness (length) of the diffusion
path
C. Ionization of Weak Acids and Weak Bases; the Henderson-
Hasselbach Equation
The electrostatic charge of an ionized molecule attracts
water dipoles and results in a polar, relatively water-soluble
and lipid-insoluble complex. Because lipid diffusion depends
on relatively high lipid solubility, ionization of drugs may
markedly reduce their ability to permeate membranes.
Weak base
• Defined as a neutral molecule that can form a
cation (a positively charged molecule) by
combining with a proton
Weak acid
• Best defined as a neutral molecule that can
reversibly dissociate into an anion (a negatively
charged molecule) and a proton (a hydrogen ion).
Protonated form of Weak Acid = Neutral , More lipid-soluble
Unprotonated form of Weak Base = Neutral form
Henerson-Hasselback equation

REFERENCES
1. Doc Valones’ PPT
2. Katzung Clinical Pharmacology Chapter 1

Glomarie’s Notes

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