PHARMACOLOGY I

Lecture \ SECOND SEMESTER

UNIT/LESSON 01: INTRODUCTION TO PHARMACOLOGY

OUTLINE

I. Pharmacology
II. Major Areas of Study In Pharmacology
A. Patient (Medical Pharmacology)
B. Environment (Toxiciology)
III. General Principles That the Student Should
Remember
IV. Pharmacodynamic Principles
A. Types of Drug-Receptor Interactions
B. Agonists That Inhibit Their Binding
Molecules
i. A Alone (Agonist)
ii. A+B (Agonist & Competitive
Inhibitor)
iii. A+C (Agonist & Allosteric Behavior)
iv. A+D (Agonist + Allosteric Inhibitor)
C. Agonists, Partial Agonists, And Inverse
Agonists
i. “Full Agonists”
ii. “Partial Agonists”
iii. “Neutral Antagonism”
iv. “Inverse Agonists”
D. Duration of Drug Action
E. Receptors and Inert Binding Sites
V. Mechanisms Of Drug Permeation
VI. Drug Development
A. In Vitro Studies
• The action of chemicals can be divided into two large domains:
B. Animal Testing
C. Clinical Testing
PATIENT (MEDICAL PHARMACOLOGY)
D. Marketing
• Pharmacokinetics
VII. Some Transport Molecules Important In
o intended and unintended targets
Pharmacology o Deals with the absorption, distribution, metabolism, and
VIII. Ionization Constants Of Some Common Drugs excretion of the drug
A. pka • Pharmacodynamics
IX. Safety Tests o Concerns the actions of the chemical on the organism
X. Additional Information o Therapeutic effect
o “What the drug does to the body”
PHARMACOLOGY o Example: taking paracetamol as an antipyretic (it should lower
fever)
• Can be defined as the study of substances that interact with living
o Taking too much medications can lead to toxic effects
systems through chemical processes (either humans or animals)
o Clinical pharmacology for humans
o Veterinary medicine for animals ENVIRONMENT (TOXICOLOGY)
• These interactions usually occur by binding a certain substance to • Concerns the effect of the chemicals on all the organisms and their
certain regulatory molecules and activating or inhibiting normal survival as a species
body processes.
• Two Branches: GENERAL PRINCIPLES THAT THE STUDENT SHOULD
o Medical Pharmacology - a science of substances used to REMEMBER
prevent, diagnose, and treat diseases • ALL substances can, under certain circumstances, be toxic.
o Toxicology - deals with toxic substances and undesirable • When not taken properly or taken too much
effects of chemicals on the living systems from individual cells • Chemicals in botanicals are no different from chemicals in
to humans to complex ecosystems. manufactured drugs except for the much greater proportion of
impurities in botanicals.
MAJOR AREAS OF STUDY IN PHARMACOLOGY o Herbal medications are good, but they usually only use
extraction with a lot of impurities.
o Synthetic drugs remove the impurities.
• All dietary supplements and all therapies promoted as health-
enhancing should meet the same standards of efficacy and safety
as conventional drugs and medical therapies.

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 UNIT/LESSON 01: INTRODUCTION TO PHARMACOLOGY
o Supplements with “No approved therapeutic claims” are not
considered as drugs.
PHARMACODYNAMIC PRINCIPLES
• Most drugs must bind to a receptor to bring about an effect.
However, at the cellular level, drug binding is only the first in a
sequence of steps:
o Drug (D) + receptor-effector (R) -> drug-receptor-effector
complex effect
▪ Example: paracetamol + COX-3 -> drug-receptor-effector
complex
o D + R -> drug-receptor complex -. Effector molecule -. Effect
▪ It will signal the effector molecule before it will have an effect;
a cascade of effects
▪ Example: gaba receptors for benzodiazepines. After binding,
it will activate a molecule that will bind to another cell that
will produce an effect.
o D + R -> D-R complex -> activation of coupling molecule ->.
Effector molecule ->. Effect
▪ Example: There will be a change in shape that will activate
another effector molecule until it will have its effect.
o Inhibition of metabolism of endogenous activator -> increased
activator action on an effector molecule -> increased effect
▪ Example: acetylcholinesterase that will break down the
acetylcholine complex can be given another drug that
inhibits the metabolism of the enzyme to increase the
activator action of the effector molecule. Thus, having an
increased effect.
A. TYPES OF DRUG-RECEPTOR INTERACTIONS
• Agonist drugs bind to and activate the receptor in some fashion,
which directly or indirectly brings about the effect.
• Pharmacologic antagonist drugs, by binding to a receptor,
compete with and prevent binding by other molecules.
o Inhibits or produces other effects other than the intended
action.
B. AGONISTS THAT INHIBIT THEIR BINDING MOLECULES
• Some drugs mimic agonist drugs by inhibiting the molecules
responsible for terminating the action of an endogenous agonist.
o Example: Opioids for pain that bind to a receptor should be
taken with another drug that can displace the drug that is
initially bound to the receptor. By doing this, it will inhibit the
toxic effect of the first drug.
• In the early 1900s, there were expansions of research in all areas
of biology. As new techniques were introduced, new information
accumulated about the drug action and substrate about that action
were obtained. We already had the concept of drug receptors.
• The drug may interact with the receptor in several ways:
o The drugs or competitive inhibitor (B) that alter the Agonist (A)
may activate the agonist binding site and compete with the
agonist.
▪ Principle in drug development: creating certain molecules
with the same shape as the agonist or parent drug so it can
displace the agonist.
o Allosteric activator (C) will bind to a certain molecule to change
the shape of a molecule to have a greater effect or prevent the
molecule to have its effect (increases or decreases the
response of the agonist)
• For example:
o Agonist (A) + Allosteric activator (C): The Allosteric activator will
increase the efficacy of the drug (agonist)
o Agonist (A) + Allosteric inhibitor (D): The Allosteric inhibitor will
decrease or not change the efficacy of the drug (agonist)
• The Sigmoid curves reflect the increase in efficacy; an increase in
affinity would result in a leftward shift of the curve
• The graph consists of the Response (y-axis) and Log Dose or dose
of drug that will be given (x-axis)
1. A ALONE (AGONIST)
• A certain dose of the agonist drug alone will have no changes in
effect
o Example: If the drug dose is 100mg, a response of 50% will just
be 50%
2. A+B (AGONIST & COMPETITIVE INHIBITOR)
• The competitive inhibitor will compete for the receptor and displace
the agonist
• The more competitive inhibitor taken by the patient, the higher
chances that it will displace the agonist
• A higher dose of agonist drug is needed to have the same effect as
the agonist drug alone
o Example: The drug must be increased to 500mg to have a 50%
effect as the agonist alone
• Competitive inhibitors will not exhibit a certain effect on an organ
3. A+C (AGONIST & ALLOSTERIC BEHAVIOR)
• Allosteric activator is given to a patient to have certain changes in
the conformation of the molecule, which will increase the effect of
the drug without increasing the dose
o Example: 100mg of drug with an allosteric activator may
increase the effect to 90% without increasing the dose
• Increased drug dose can be more toxic, thus drugs that can alter
the molecule are developed
o There will be no need to increase the drug dose to have a
4. A+D (AGONIST + ALLOSTERIC INHIBITOR)
• The effect will decrease because the action will be inhibited
• Due to the allosteric inhibitor, the effect will decrease without
decreasing the dose
o Example: 100g of the drug will only have a 20% effect
• Researches on Pharmacology such as Antagonism and Agonism
revolve around these concepts for drugs to be less toxic
• In antipsychotics, same classification of medications (typical
antipsychotics are risperidone, olanzapine, and clozapine) have
different doses
o Example: 2mg of risperidone has the same effect as 10mg of
olanzapine, a higher dose of olanzapine is needed to reach the
same effect as risperidone
o Drugs have different structures and thus have different effects
to the body
C. AGONISTS, PARTIAL AGONISTS, AND INVERSE
AGONISTS
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 UNIT/LESSON 01: INTRODUCTION TO PHARMACOLOGY
• To function as a receptor, an endogenous molecule must first be
selective in choosing ligands (drug molecules) to bind;
o Example: If paracetamol is taken, it does not necessarily mean
that all receptors in the body will bind to it
• second, it must change its function upon binding in such a way
that the function of the biologic system (cell, tissue, etc) is altered
o If the drug does not change the function, the drug has no effect
o Drugs or molecules that bind to a certain molecule and exhibit
no effect is useful in toxicology, when the drug effect must be
decreased
▪ The agonist must be displaced from the receptor so that it
will not bind and result to a greater effect that can be
detrimental to the patient

MECHANISMS OF DRUG PERMEATION

• The drug must traverse the drug layer to have its effect

• Figure 1-3 describes a useful model of drug receptor interaction

o The hypothetical receptor is able to assume two conformations:
▪ Ri conformation - inactive and produces no effect, even
when combined with a drug molecule
▪ Ra conformation - can activate a down-stream mechanism
that produce a small observable effect, even in the absence • A) Drugs may diffuse passively through aqueous channels in the
of drug (constitutive activity) intercellular junctions (eg, tight junctions)
• “Constitutive Activity” • B) Other drugs should pass through a lipid cell membrane
o Concept of Ra activation, it can still activate a certain o Cells are lipid layers, thus more lipid-soluble drugs have a
mechanism and produce a small observable effect/change in higher chance to pass through the cell
the absence of drug o Some developed drugs are made to be more lipid-soluble for
• In the absence of drugs, the two isoforms Ri and Ra are in higher chances to be absorbed and have a therapeutic effect
equilibrium, and the Ri is favored • C) Drugs with the appropriate characteristics may be transported
1. “FULL AGONISTS” by carriers into or out of cells
• When a full agonist drug is given (i.e. morphine, an analgesic), it o These are the active transport mechanisms
will favor or have a higher affinity with the Ra conformation o Certain transporters are needed for it to enter and leave the cell
• Mass action thus result to the formation of the Ra-D (receptor-drug) • D) Very impermeant drugs may also bind to cell surface receptors
complex with a much larger observed effect (dark binding sites), be engulfed by the cell membrane
2. “PARTIAL AGONISTS” (endocytosis),
o Molecules that cannot pass through the cell will be engulfed by
• Have an intermediate affinity to both Ri and Ra (equally bind) the cell membrane
o Example: If the effect is 90% for the full agonist, the effect of • D.1) and then be released inside the cell or expelled via the
the partial agonist may only be 45% membrane-limited vesicles out of the cell into the extracellular
• Has a minimal effect space (exocytosis)
3. “NEUTRAL ANTAGONISM” o So it can pass through the cell membrane
• Have equal affinity for both receptor forms (Ri and Ra) and maintain • These mechanisms are used by the drug to pass through the cell
the same level of constitutive activity membrane.
• Constitutive activity has a minimal effect, but the effect is not o No permeation, no effect
enough to be therapeutic ▪ Because almost all of drug receptors are INSIDE the cell.
4. “INVERSE AGONISTS”
• Have higher affinity for the Ri
DRUG DEVELOPMENT
• It will reduce the constitutive activity and may produce a contrasting
physiologic result
o Example: For tachycardia, when an inverse agonist is given the
heart may experience bradycardia
o Examples of inverse agonists are benzodiazepines
(antiepileptics such as diazepam, valium), which binds to the
gaba receptor but has a negative effect
o In epilepsy, electrical signals are experienced during a seizure
and these drugs can reduce these effects
• There are times when the needed drug effect is the opposite, thus
certain drugs are developed to counter that action

D. DURATION OF DRUG ACTION

• Termination of drug action can result from several processes
• In some cases, the effect lasts only as long as the drug occupies
the receptor, and dissociation of drug from the receptor IN VITRO STUDIES
automatically terminates the effect • Laboratory work, makes use of plates (in vitro: non-living
organisms)
E. RECEPTORS AND INERT BINDING SITES

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 UNIT/LESSON 01: INTRODUCTION TO PHARMACOLOGY
• Lead compound: will be formed from biologic products or from Increased expression
chemical synthesis, optimization confers resistance to
• Preformulation studies: tests extracted materials/chemicals to see certain anticancer
if the extract is contagious or not drugs.
o Example: from Senna leaves
• Average of 1 to 2 years Inhibition increases
Transport of many
blood levels of digoxin
MDR1 xenobiotics out of
ANIMAL TESTING (cardiac toxicity)
cells
• Formulation of dosage form (eg. syrup, tablet, cream)
• To test for efficacy, selectivity, mechanism Useful for preventing
• There is a certain animal selected that can mimic physiological toxicities because they
activity of humans for a certain activity transport xenobiotics
o Antipyretic activity : rabbits out of the cell
o Anesthesia : rats, mice
• Average of 2 to 4 years Confers resistance to
Leukotriene
MRP1 certain anticancer and
secretion
CLINICAL TESTING antifungal drugs
• IND (Investigational New Drug)
• Drug metabolism and safety assessment IONIZATION CONSTANTS OF SOME COMMON DRUGS
• Randomized controlled trials (double blind studies) DRUG pK DRUG pK DRUG pK
o Unethical because patients either receive the drug or placebo a1 a1 a1
to ensure that the process has no biases Weak bases
Weak acids Weak bases
• Phase 1 (cont’d)
o 20 to 100 subjects Acetaminop Albuterol 9.3 Isoproterenol 8.6
9.5
o Is it safe, pharmacokinetics? hen (salbutamol)
• Phase 2 Acetazolami
9.4, Lidocaine 7.9
o 100 to 200 patients 7.2 Allopurinol 12.
de
o Does it work in patients? Does it reach the therapeutic effect? 32
Is the effect significant? Ampicillin 2.5 Alprenolol 9.6 Metaraminol 8.6
• Phase 3 Aspirin 3.5 Amiloride 8.7 Methadone 8.4
o 1000 to 6000 people Chlorothiazi 6.8, 6.6 Methampheta 10.
Amiodarone
o Does it work, double blind? de 9.42 mine 0
o Double blind: neither researcher and subject does not know the Chlorpropa Amphetamin 9.8 Methyldopa 10.
5.0
content of the sample mide e 6
• AFTER PHASE 3: NDA (New Drug Application) Ciprofloxaci 6.1, 9.7 Metoprolol 9.8
Atropine
• Average of 4 to 5 years n 8.72
Cromolyn 2.0 Bupivacaine 8.1 Morphine 7.9
MARKETING Etharcrynic
2.5
Chlordiazepo 4.6 Nicotine 7.9,
• Phase 4 or Postmarketing Surveillance acid xide 3.12
• To observe adverse effects, side effects, long term effects, chronic 10. Norepinephrin 8.6
effects (eg. Drugs that are being pulled out of the market even after Furosemide 3.9 Chloroquine 8 e
passing clinical trials) 8.4
• Innovator drugs - expensive Ibuprofen
4.4, Chlorpromazi 9.2 Pentazocine 7.9
o Granted 10 years patency as the sole manufacturer of the 5.22 ne
newly discovered drug to make bawi the previous gastos Levodopa 2.3 Clonidine 9.3 Phenylephrine 9.8
o When the patent expires, the other companies can have the Methotrexat 8.3 Physostigmin 7.9,
4.8 Clonidine
apply for a monograph and manufacture the drug (Generic e e 1.82
drugs) 2.2, 8.5 Pilocarpine 6.9,
Methyldopa Cocaine
• Average of 10 years 9.22 1.42
Penicillamin 8.2 Pindolol 8.6
1.8 Codeine
SOME TRANSPORT MOLECULES IMPORTANT IN e
PHARMACOLOGY Pentobarbit 8.2 Procainamide 9.2
8.1 Cyclizine
al
TRANSPORTER PHYSIOLOGIC PHARMACOLOGIC
Phenobarbit 10. Procaine 9.0
FUNSTION SIGNIFICANCE 7.4 Desipramine
al 2
Norepinephrine Target cocaine and
Phenytoin 8.3 Diazepam 3.0 Promethazine 9.1
NET reuptake from some tricyclic
Propylthiour Diphenhydra 8.8 Propranolol 9.4
synapse antidepressants 8.3
acil mine
Target of selective
Salicylic Diphenoxylat 7.1 Pseudoephed 9.8
Serotonin reuptake serotonin reuptake 3.0
SERT acid e rine
from synapse inhibitors and some
9.6 Pyrimethamin 7.0-
tricyclic antidepressants Sulfadiazine 6.5 Ephedrine
e 7.33
Transport of
dopamine and Sulfapyridin 8.7 Quinidine 8.5,
8.4 Epinephrine
e 4.42
norepinephrine Target of reserpine and
VMAT Theophyllin 6.3 Scopolamine 8.1
into adrenergic tetrabenazine 8.8 Ergotamine
vesicles in nerve e
endings 8.0, Strychnine 8.0,
Tolbutamide 5.3 Fluphenazine
3.92 2.32

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 UNIT/LESSON 01: INTRODUCTION TO PHARMACOLOGY
7.1 Terbutaline
Warfarin 5.0 Hydralazine
Imipramine 9.5 Thioridazine
PKA
• indicates the acidity level of the drug
• Lower pKa = strong acid, full dissociation on water
• Drug examples:
o The reason why some drugs are given at different doses (eg.
500mg, 3x a day) is because of their pKa variations
▪ Acetaminophen (9.5) given as 500mg
SAFETY TESTS
TYPE OF TESTS
APPROACH AND
GOALS
Usually two species, two
routes, Determine the no-
effect dose and the
maximum tolerated dose.
Acute toxicity
In some cases, determine
the acute dose that is
lethal in approximately
50% of animals.
Three doses, two species.
Two weeks to 3 months of
testing may be required
Subacute or before clinical trials. The
subchronic longer the duration of
toxicity expected clinical use, the
longer the subacute test,
Determine biochemical
physiological effects
Rodents and at least one
nonrodent species
for >6months. Required
when a drug is intended to
be used in humans for
Chronic toxicity
prolonged periods. Usually
run concurrently with
clinical trials. Determine
the same end points as
subacute toxicity tests.
Two species, usually one
rodent and rabbits. Test
Effect on effects on animal mating
reproductive behavior, reproduction,
performance parturition, progeny, birth
defects, postnatal
development
Two years, two species.
Required when a drug is
Carcinogenic intended to be used in
potential humans for prolonged
periods. Determine gross
and histologic pathology.
Tests effects on genetic
stability and mutations in
bacteria (Ames test) or
Mutagenic
mammalian cells in
potential
culture; dominant lethal
test and clastogenicity in
mice.
ADDITIONAL INFORMATION
• Acute toxicity
o Lethal dose 50 (LD50) - what is the dose that we give to kill the
50% of the population
10. ▪ Maximum dose of 3000mg or 3g of paracetamol can be
1 given to induce toxicity
9.5 • Chronic toxicity
o The drug may be nontoxic acutely, but becomes toxic when
taken for longer periods (eg. 6-9 months)
o Example species used:
▪ Rodents = rats
▪ Dogs were used before for tests
▪ Chicks
• Effect on reproductive performance
o Rabits and rodents are very sexually active, good for this study
o Drugs that are categorized (A,B,C,D,X)
o Category X - teratogenic
▪ Examples: valproic acids, bipolar drugs, retinoids, acne
medications
▪ Vitamin E - should not be taken 6 months before and during
pregnancy to avoid loss of limbs of the fetus, defects
FDA Drug Risk Classification
CATEGORY DESCRIPTION
Controlled studies in
A humans show no risk to
the fetus
No controlled studies
have been conducted in
B humans; animal studies
show no risk to the
fetus
No controlled studies
C have been conducted in
animals or humans
Evidence of human risk
to the fetus exists;
however, benefits may
D
outweigh risks in certain
situations
Controlled studies in
both animals and
humans demonstrate
X fetal abnormalities; the
risk in pregnant women
outweighs any possible
benefit.
• Carcinogenic potential
o Always need to check changes in tissue appearances
• Mutagenic potential
o Check genetic stability for mutations
REFERENCES
Introduction: The Nature of Drugs & Drug Development & Regulation
pdf
Introduction to Pharmacology Recorded Lecture
KBA, CKB, GLG, AKS, GIV | 2F-PH 5