BASIC

PHARMACOLOGY
for Dentistry

Jo-Ann S. Belotindos,RPh,MPH,MPP
College of Pharmacy, SWU-PHINMA
 Learning Objectives:
• At the end of the session, the student be able to:
• Define pharmacology, toxicology, drug, pharmacogenomics, pharmacokinetics,
pharmacodynamics.
• Describe the principles of pharmacokinetics and principles of pharmacodynamics.
• Understand the physical nature of drugs
• Describe drug molecule – receptor interaction

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 INTRODUCTION

Definitions Pharmacokinetics
Pharmacodynamics

Permeability /
Absorption
Nature of
Distribution Drugs

Receptors,
Metabolism
Receptors
Elimination sites

Inert binding
sites
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CASE STUDY
 PHARMACOLOGY

= the study of substances that interact with living systems through chemical
processes, especially by binding to regulatory molecules and activating or
inhibiting normal body processes.

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• these substances maybe chemicals administered to achieve beneficial
therapeutic effect on some process within the patient or for their toxic
effects on regulatory processes in parasites infecting the patient.

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MEDICAL PHARMACOLOGY

= defined as the science of substances

used to prevent, diagnose, and treat
disease.

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TOXICOLOGY

= branch of pharmacology which deals

with the undesirable effects of
chemicals on living systems, from
individual cells to complex ecosystems.

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• New drugs are added every year; they are needed for several reasons:
(1) increasing resistance by bacteria and other
parasites;
(2) discovery of new target processes in diseases
that have not been adequately treated; and
(3) recognition of new diseases.
Furthermore, a dramatic increase has occurred in the number of large
molecule drugs (especially antibodies) approved during the last two
decades.

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The History of Pharmacology

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Pharmacogenomics —the relation of the individual's
genetic makeup to his or her response to specific
drugs is becoming an important part of
therapeutics.

• Decoding of the genomes of many species – from

bacteria to humans – led to the recognition of
unsuspected relationships between receptor families
and the ways that receptor proteins have evolved.
• Discovery of small segments of RNA (siRNAs, miRNAs, ANOs)
--- next major wave of advances in therapeutics.

siRNAs – small interfering RNAs

miRNAs – micro RNAs
ANOs – antisense oligonucleotides
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General principles that the student should remember:

(1) that all substances can, under certain circumstances, be toxic;

(2) that the chemicals in botanicals (herbs and plant extracts,
“nutraceuticals”) are no different from chemicals in manufactured
drugs except for the much greater proportion of impurities in
botanicals; and

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(3) that 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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• That is, there should be NO artificial separation between scientific medicine
and "alternative" or "complementary" medicine.

• Ideally, ALL nutritional and botanical substances should be

tested by the same randomized controlled trials (RCTs) as
synthetic compounds.

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 The NATURE of DRUGS:
DRUG
• any substance that brings about a change in biologic function through its
chemical actions.
• 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 molecule is called a receptor .

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• Drugs maybe synthesized within the body (eg.
Hormones) or maybe chemicals not synthesized in the
body, ie. Xenobiotics (xenos – “stranger”)

• Poisons are drugs that have almost exclusively harmful effects. (Paracelsus
– famously stated “the dose makes the poison” --- any substance can be harmful if
taken in the wrong dosage)

• Toxins are defined as poisons of biologic origin,

synthesized by plants or animals

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The Physical Nature of Drugs

To interact chemically with its receptor, a drug

molecule must have the:
• Appropriate size
• Electrical charge
• Shape
• Atomic composition

FURTHERMORE…

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• A drug is often administered at a location distant
from its intended site of action, eg, a pill is given
orally to relieve a headache.

• 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.

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 The physical nature of drugs:

• drugs maybe:
• solid @ room temp. (ex. aspirin, atropine),
• liquid (ex. nicotine, ethanol),
• gaseous (ex. nitrous oxide, nitric oxide, xenon)

These factors often determine the best route of

administration.

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To interact chemically with its receptor, a DRUG molecule must have the :

a. appropriate SIZE

varies from very small (lithium ion MW7) to very

large ( Alteplase MW59,050).

- 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.

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Drugs interact with receptors by means of chemical
forces or bonds.
These are of 3 major types:
1. COVALENT bonds – are very strong and in many
cases not reversible under biologic conditions.
(Aspirin [NSAIDs] – irreversibly blocks COX)

2. ELECTROSTATIC bonds – more common but are

weaker than covalent bonds.

3. HYDROPHOBIC bonds – are usually quite weak and

are important in the interactions of highly lipid
soluble drugs.

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b. electrical charge

c. shape
the shape of a drug molecule must be such
as to permit binding to its receptor site.
Optimally, the drug shape complementary
to that of the receptor site in the same
way that a key is complementary to a lock.
d. atomic composition

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Drug – Receptor Binding

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DRUG – BODY INTERACTIONS
• PHARMACODYNAMICS – the actions of the drug on the
body.
• These determine the group in which the drug is classified,
and play the major role in deciding whether the group is an
appropriate therapy for a particular symptom or disease.

• PHARMACOKINETICS – the actions of the body on the

drug.
• Govern the Absorption, Distribution, and Elimination of
drugs and are of great practical importance in the choice
and administration of a particular drug for a particular
patient.
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 what is
often a complex sequence of steps…

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• Drug (D) + receptor-effector (R) drug-receptor-
effector complex effect

•D + R drug-receptor complex effector molecule

effect

• D + R D – R complex activation of coupling

molecule effector molecule effect

• Inhibition of metabolism of endogenous activator

increased activator action on an effector molecule
increased effect

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 PHARMACODYNAMIC PRINCIPLES

A. Types of Drug-Receptor Interactions

a. AGONIST – drugs bind to and activate the receptor in some fashion,

which directly or indirectly brings about the effect.

b. ANTAGONIST – by binding to a receptor, prevent binding by other

molecules.

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 PHARMACODYNAMIC PRINCIPLES

B. Agonist that Inhibit their Binding Molecules

• Some drugs mimic agonist drugs by inhibiting the molecules responsible for
terminating the action of an endogenous agonist.
• For example, AchE inhibitors, by slowing the destruction
of endogenous Ach, cause cholinomimetic effects

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C. Agonists, Partial Agonists, and Inverse Agonists

As describe in Figure 1–3 [1-2], a model of drug-

receptor interaction.

Partial agonist – bind to the same receptors and activate them

in the same way but do not evoke as great a response, no matter
how high the concentration.
Inverse agonist –is a ligand that binds to the same
receptor-binding site as an agonist and not only
antagonizes the effects of an agonist but exerts the
opposite effect by suppressing spontaneous receptor
signaling (when present).

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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 automatically terminates the effect.
• In many cases, however, the action may persist after the
drug has dissociated because some coupling molecule is
still present in activated form.

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• In the case of drugs that bind covalently to the receptor site, the
effect may persist until the drug-receptor complex is destroyed and
new receptors or enzymes are synthesized.

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 PHARMACODYNAMIC PRINCIPLES
E. Receptors and Inert Binding Sites

• To function as a receptor, an endogenous molecule must

first be selective in choosing ligands (drug molecules) to
bind.
• The SELECTIVITY characteristic is required to avoid constant activation of the receptor by promiscuous
binding of many different ligands.

• Second, it must change its function upon binding in such

a way that the function of the biologic system (cell,
tissue) is altered.

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For SAS 2

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PHARMACOKINETICS

• The goal of therapeutics is to achieve a desired

beneficial effect with minimal adverse effects.
• When a medicine has been selected for a patient, the
clinician must determine the dose that most closely
achieves this goal.
• A rational approach to this objective combines the
principles of pharmacokinetics with
pharmacodynamics to clarify the dose-effect
relationship.

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• Pharmacodynamics governs the concentration-effect part
of the interaction, whereas;
• Pharmacokinetics deals with the dose-concentration part.
• The pharmacokinetic processes of absorption,
distribution, and elimination determine how rapidly
and for how long the drug will appear at the target
organ.
• The pharmacodynamic concepts of maximum
response and sensitivity determine the magnitude of
the effect at a particular concentration.

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Figure 3 – 1

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PHARMACOKINETICS
=the actions of the body on the
drug.

= this govern the Absorption, Distribution, and Elimination of

drugs and are of great practical importance in the choice and
administration of a particular drug for a particular patient.

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 2 BASIC PHARMACOKINETIC
PARAMETERS:
1. VOLUME of DISTRIBUTION (V)
- the measure of the apparent space in
the body available to contain the drug.

- relates the amount of drug in the body to

the concentration of drug (C) in blood or plasma.
V = amount of drug in the body
C

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• The volume of distribution may be defined with
respect to blood, plasma, or water (unbound drug),
depending on the concentration used in equation.

• Volume of distribution can vastly exceed any

physical volume in the body because it is the
volume apparently necessary to contain the
amount of drug homogeneously at the
concentration found in the blood, plasma, or water.

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• Drugs with very high volumes of distribution have
much higher concentrations in extravascular tissue
than in the vascular compartment, ie, they are not
homogeneously distributed.

• Drugs that are completely retained within the

vascular compartment have a minimum possible
volume of distribution equal to the blood
component in which they are distributed, for a drug
that is restricted to the plasma compartment.

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2. CLEARANCE
- the measure of the ability of the body
to eliminate the drug.

- is the factor that predicts the rate of

elimination in relation to the drug
concentration.

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-maybe defined with respect to blood
(CLb),plasma (CLp), or unbound in water
(CLu), depending on the concentration
measured.

- The two major sites of drug elimination are the

kidneys and the liver.

- Clearance of unchanged drug in the urine represents

renal clearance.
- Within the liver, drug elimination occurs via
biotransformation of parent drug to one or more
metabolites, or excretion of unchanged drug into the
bile, or both.
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- dividing the rate of elimination at each organ by the conc. of drug
presented to it yields the respective clearance at that organ.
- Added together, these separate clearances equal total systemic clearance.

CL = rate of elimination
C

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FORMULAS:
a. CL renal = rate of elimination (kidney)
C

b. CL liver = rate of elimination (liver)

C

c. CL other = rate of elimination (other)

C

• CL systemic = CL renal + CL liver + CL other

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Biological Half-life (t 1/2)
• is the time required to change the amount of drug
in the body by one-half during elimination.
• the most useful in designing drug dosage regimens.
• The time course of drug in the body will depend on
both the volume of distribution and the clearance:
t ½ = 0.7 x V
CL

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• Half-life useful because it indicates the time required to
attain 50% of steady state—or to decay 50% from
steady-state conditions—after a change in the rate of
drug administration.

• Disease states can affect both of the physiologically

related primary pharmacokinetic parameters: volume
of distribution and clearance.

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 Drug Accumulation
• With repeating drug doses, the drug will accumulate in
the body until dosing ceases.
• Practically: if the dosing interval is shorter than four
half-lives, accumulation will be detectable.
• Accumulation: inversely proportional to the fraction of
the dose lost in each dosing interval.
• The fraction lost is 1 minus the fraction remaining just
before the next dose. The fraction
remaining can be predicted from the dosing interval
and the half-life.
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• For a drug given once every half-life, the accumulation
factor is 1/0.5, or 2.

• The accumulation factor predicts the ratio of the

steady-state concentration to that seen at the same
time following the first dose.

• Thus, the peak concentrations after intermittent doses

at steady state will be equal to the peak concentration
after the first dose multiplied by the accumulation
factor.

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Bioavailability

• Definition: fraction of unchanged drug reaching the

systemic circulation following administration by any
route.

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• The area under the blood concentration time curve
(AUC) is a common measure of the extent of
bioavailability for a drug given by a particular route.

• For an IV dose of the drug, bioavailability is assumed to

be equal to unity.

• For a drug administered orally, bioavailability may be

less than 100% for 2 main reasons: incomplete extent
of absorption across the gut wall and first-pass
elimination by the liver.

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• Check table 3 – 3 Routes of administration, Bioavailability
(%) and general characteristics.

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 ROUTES of ADMINISTRATION:

A. ENTERAL:
1. ORAL
= most common and require the most
complicated pathway to the tissues.
= most variable
= offers maximum convenience, but
absorption may be slower and less
complete than when parenteral routes are
used.

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= some drugs are absorb in the stomach but
DUODENUM is often the major site because of its
larger absorptive surface.
= ingestion of foods can influence absorption.
Presence of food in the stomach delays gastric
emptying time (ex. PCN) so that drugs that are
destroyed by acid become unavailable for
absorption.
= most drugs are absorb from the GIT enter the portal
circulation and encounter the liver before they are
distributed into the general circulation.

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Hepatic ‘First-Pass’ Metabolism
• Affects orally administered drugs
• Drug absorbed into portal circulation, must pass
through liver to reach systemic circulation
• May reduce availability of drug
• Ex. 90% of nitroglycerin is cleared during a single
passage thru the liver.

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2. SUBLINGUAL / BUCCAL
= sublingual (place under the tongue)

= buccal route (in the pouch between gums and cheeks)

= allows the drug to diffuse into the capillary network

and to enter the systemic circulation directly.

= bypass the intestine and liver and not activated by

metabolism.

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3. RECTAL (suppository)
= offers partial avoidance of the first pass effect.
Because suppositories tend to migrate upward in the
rectum and absorption from this higher location is
partially into the portal circulation.

= prevent the destruction of the drug by intestinal

enzymes or by low pH of the stomach (also for
sublingual!)

= useful if the drug induces vomiting when given orally.

= commonly used to administer ANTIEMETIC agents.

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Parenteral Route
• Intravenous*
• Intramuscular
• Subcutaneous
• Intradermal
• Intrathecal
• Intraarticular
*Fastest delivery into the blood circulation

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B. PARENTERAL:
= use for drugs that are poorly absorbed from the
GIT.
= example: INSULIN (unstable in GIT)
= use for treatment of unconscious patient – which
requires rapid onset of action under circumstances.
= provides the most control over the actual dose of
drug delivered to the body.
= 3 major parenterals:
IV
IM
SC
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1. INTRAVASCULAR (IV)
= IV is the most common.

= use for drugs that are not absorb orally!

= IV injection of some drugs may introduce bacteria thru
contamination at the site of injection, induce hemolysis or
cause other adverse reactions by the too rapid delivery of high
concentration of the drug.

= avoids GIT / 1st – pass metabolism by the liver.

= permits a rapid effect and a maximal degree of control over

the circulating levels of the drug.
= unlike oral drugs, it cannot be recalled by strategies such as
emesis or binding to activated charcoal.

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2. INTRAMUSCULAR (IM)
= can be aqueous solution or specialize depot preparation (
often a suspension of drug in a non aqueous vehicle like
ethylene glycol or peanut oil)

= first pass metabolism is avoided, but anticoagulants such

as Heparin cannot be given by this route because they may
cause bleeding (hematomas) in the muscle.

= absorption of drugs in aqueous solution is fast, whereas

from depot preparation is slow.

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= as the vehicle diffuses out of the
muscle, the drug precipitates at the site of injection.
Then the drug dissolves slowly, providing a sustained
dose over an extended period of time.

Examples; in depot preparation:

Haloperidol decanoate ( slow diffusion
to the muscle produces an extended
neuroleptic effect)
Hepa B vaccine
Tetanus toxoid (Tetavax)
Verorab ( rabies vaccine)

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3. SUBCUTANEOUS (SC)
= offers slower absorption than the IM route; slower
than IV
= large volume bolus doses are less feasible but
heparin does not cause hematomas when
administered by this route.
= minimizes the risks associated with IV injections.
= First-pass metabolism is avoided.
examples: epinephrine ( act as local
vasoconstrictor and decreases removal
of a drug such as LIDOCAINE, from the site
of administration); insulin

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Topical Route
• Skin (including transdermal patches)
• Eyes
• Ears
• Nose
• Lungs (inhalation)
• Vagina

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OTHERS:
1. INHALATION
= provides rapid delivery of a drug across
the large surface area of mucous
membrane of the respiratory tract and pulmonary
epithelium.
= effective and convenient for patients
with respiratory complaints.
examples: Budesonide (Budecort inhaler)
Flixotide (Fluticasone propionate)
Easily volatilized many anesthetics

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2. INTRANASAL
= examples: Desmopressin is administered
intranasally in the treatment of diabetes insipidus.
= Calcitonin, a peptide hormone, for the treatment of
osteoporosis is also available in nasal spray.
= Cocaine, generally taken by sniffing

3. INTRATHECAL / INTRAVENTRICULAR
= introduces drugs directly to the cerebrospinal fluid
(CSF).
= examples; Methotrexate for ALL
Amphotericin B to treat
cryptococcal meningitis

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4. TOPICAL
= use when local effect of the drug is desired.
= this route includes application to the skin or to the
mucous membrane of the eye, nose, throat, airway, or
vagina for local effect.
examples:
Clotrimazole, treatment of dermatophytosis
Atropine, instill directly to the pupil to
dilate eyes and permit
measurement of refractive errors.

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5. TRANSDERMAL
= achieves systemic effects by application of drugs
to the skin.
= the rate of absorption varies, depending on the
physical characteristics of the skin at the site of
application.
ex. Nitroglycerin patch

= first pass effect is avoided.

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Reasons for different Routes of
Administration:

• For convenience – oral drugs

• To maximize concentration at the site of action and
minimize it elsewhere (topical)
• To prolong the duration of drug absorption
(transdermal)
• To avoid the first pass effect

Alternative RoA & the 1st-pass effect

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• Avoiding the first-pass effect:
• sublingual (e.g. nitroglycerin)-- direct access to systemic circulation
• transdermal
• use of rectal suppositories in the lower rectum enter vessels that drain into the
inferior vena cava, thus bypassing the liver (only about 50%).
• inhalation: first-pass pulmonary loss by excretion or metabolism may occur.

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 Extraction ratio & First-pass effect
• Systemic clearance is not affected by bioavailability.
However, clearance can markedly affect the extent of
availability because it determines the extraction ratio.
• Other drugs that are highly extracted by the liver include
isoniazid,morphine, propranolol, verapamil, and several
tricyclic antidepressants.
• Drugs with high extraction ratios will show marked
variations in bioavailability between subjects because of
differences in hepatic function and blood flow.

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• For drugs that are highly extracted by the liver, bypassing
hepatic sites of elimination (eg, in hepatic cirrhosis with
portosystemic shunting) will result in substantial increases
in drug availability.

• For drugs that are poorly extracted by the liver (for which
the difference between entering and exiting drug
concentration is small), shunting of blood past the liver will
cause little change in availability.

• Drugs that are poorly extracted by the liver include

chlorpropamide, diazepam, phenytoin, theophylline,
tolbutamide, and warfarin.

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THE TIME COURSE of DRUG EFFECT

• IMMEDIATE EFFECTS – drug effects are directly related to

plasma concentrations.
• DELAYED EFFECTS

• CUMMULATIVE EFFECTS

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 DELAYED EFFECTS
• Changes in drug effects are often delayed in relation to changes in plasma
concentration.

• This delay may reflect the time required for the drug to
distribute from plasma to the site of action.

• The delay due to distribution is a pharmacokinetic

phenomenon that can account for delays of a few
minutes.

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• Some drugs bind tightly to receptors, and it is the half-
life of dissociation that determines the delay in effect,
eg, for digoxin.

• A common reason for more delayed drug effects

especially those that take many hours or even days to
occur is the slow turnover of a physiologic
substance that is involved in the expression of the
drug effect.
• Example: Warfarin inhibits vit. K epoxidase in the liver
(inhibition of enzyme is closely related to the plasma
concentrations of warfarin)

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 CUMULATIVE EFFECTS
• The renal toxicity of aminoglycoside antibiotics (eg,
gentamicin) is greater when administered as a constant
infusion than with intermittent dosing.
• It is the accumulation of aminoglycoside in the renal
cortex that is thought to cause renal damage.
• The effect of many drugs used to treat cancer also
reflects a cumulative action.

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 The Target Concentration Approach to
Designing a Rational Dosage Regimen
• MAINTENANCE DOSE
• Drugs are administered to maintain a steady state
concentration in the body.
(just enough drug is given in each dose to replace the drug
eliminated since the preceding dose)
• Clearance is
the most important pharmacokinetic term to be
considered in defining a rational steady-state drug dosage
regimen.
• At steady state, the dosing rate (“rate in”) must equal the
rate of elimination (“rate out”).
• LOADING DOSE
• Promptly raises the concentration of drug in plasma to the target
concentration.

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 Plasma Protein Binding: Is It Important?

• Plasma protein binding is often mentioned as a factor

playing a role in pharmacokinetics, pharmacodynamics,
and drug interactions.

• if a drug is displaced from plasma proteins it would

increase the unbound drug concentration and increase
the drug effect and, perhaps, produce toxicity.

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• Drug displaced from plasma protein will be distribute
throughout the volume of distribution, so that a 5%
increase in the amount of unbound drug in the body
produces at most a 5% increase in pharmacologically
active unbound drug at the site of action.

• Second, when the amount of unbound drug in plasma

increases, the rate of elimination will increase and
after four half-lives the unbound concentration will
return to its previous steady state value.

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• The clinical importance of plasma protein binding
is only to help interpretation of measured drug
concentrations.

• When plasma proteins are lower than normal, then

total drug concentrations will be lower but
unbound concentrations will not be affected.

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82
 Factors affecting protein binding:
1. Albumin concentration: Drugs such as phenytoin,
salicylates, and disopyramide (weak acid drugs) are extensively
bound to plasma albumin. Albumin levels are low in many
disease states lower total drug concentrations.

2. Alpha1-acid glycoprotein concentration: α1-acid

glycoprotein is an important binding protein with binding sites
for drugs such as quinidine, lidocaine, and propranolol (weak
base drugs) It is increased in
acute inflammatory disorders and causes major changes in total
plasma concentration of these drugs even though drug
elimination is unchanged.

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3. Capacity-limited protein binding:

The binding of drugs to plasma proteins is capacity-limited.

Therapeutic concentrations of salicylates and prednisolone
show concentration-dependent protein binding.
Because unbound drug concentration is determined by dosing
rate and clearance—which is not altered, in the case of these
low-extraction-ratio drugs, by protein binding—increases in
dosing rate will cause corresponding changes in the
pharmacodynamically important unbound concentration.

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4. Binding to RBCs:
drugs such as cyclosporine and tacrolimus bind
extensively inside RBC.
A decrease in RBC concentrationwill cause whole blood
concentration to fall.

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Pharmacokinetic Processes

“LADME” is key

Liberation Metabolism

Absorption Excretion

Distribution
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Liberation

• Applies to drugs given orally

• Components
• Release of drug from pill, tablet, capsule
• Dissolving of active drug in GI fluids

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Absorption

• Movement from administration site into circulation

• The absorption of a drug through the mucosal lining of the GIT or

through capillary walls depends on the physical and chemical
properties of the drug.

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Pharmacokinetics: Distribution
The transport of a drug in the body by the bloodstream to its site of
action.
• Rate of perfusion
• Ability to cross membranes
• Blood-brain barrier
• Placental barrier
• Plasma Protein-binding
• Water soluble vs. fat soluble
• Areas of rapid distribution: heart, liver, kidneys, brain
• Areas of slow distribution: muscle, skin, fat

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 Blood-Brain Barrier

The blood brain barrier

consists of cell tightly packed
around the capillaries of the
CNS.
What characteristics must a
drug possess to easily cross
this barrier?

Non-protein bound, non-ionized,

and highly lipid soluble
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Pharmacokinetics: Metabolism
(Drug Biotransformation)

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 Pharmacokinetics: Metabolism
(Drug Biotransformation)

The biologic transformation of a drug into an inactive

metabolite, a more soluble compound, or a more
potent metabolite.
 Liver (main organ)
 Kidneys
 Lungs
 Plasma
 Intestinal mucosa
 Skin

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• Metabolic products are often less
pharmacodynamically active than the parent drug
and may even be inactive.

• However, some biotransformation products have

enhanced activity or toxic properties.

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Pharmacokinetics:
DRUG EXCRETION
- is the process by which a drug or metabolite is eliminated from the
body.

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Routes of elimination:
1. KIDNEY = most important organ for excretion of drugs.
= primary site

● Excretion of drugs and their metabolites via the urine involves 3

processes:
 Passive glomerular filtration
 Active tubular secretion
 Passive tubular reabsorption

2. the BILIARY TRACT and the FECES

3. Other routes which includes:

- expired air - saliva - breast milk
- sweat - tears

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For SAS 1
Pharmacodynamics

• The biochemical and physiologic mechanisms of drug action

What the drug

does when it gets there.

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Pharmacodynamics

= The actions of the drug on the

body.
= this determine the group in
which the drug is classified and
play the major role in deciding
whether that group is appropriate
therapy for a particular symptom
or disease.
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Pharmacodynamics:
Mechanisms of Action

• Receptor interaction
• Enzyme interaction
• Nonspecific interactions

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RECEPTORS
• The component of a cell or organism that interacts with a drug and
initiates the chain of biochemical events leading to the drug`s
observed effects.

• The receptor concept has important practical consequences for the

development of drugs and for arriving at therapeutic decisions in
clinical practice.

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RECEPTORS...
1. Largely determine the quantitative relations
between dose or concentration of drug and
pharmacologic effects (affinity for binding);

2. Are responsible for selectivity of drug action

(molecular size, shape, electrical charge determine whether
it will bind to a particular receptor among the different
binding sites available in a cell, tissue, or patient;

3. Mediate the actions of both pharmacologic

agonists and antagonists.

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• Most receptors are proteins.

• "orphan" receptors - so
called because their ligands are
presently unknown, which may prove to be useful
targets for the development of new drugs.

• The best-characterized drug receptors are Regulatory

proteins, which mediate the actions of endogenous
chemical signals such as neurotransmitters, autacoids,
and hormones.

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• Other classes of proteins that have been clearly
identified as drug receptors include Enzymes, which
may be inhibited (or, less commonly, activated) by
binding a drug (eg, dihydrofolate reductase, the
receptor for the antineoplastic drug Methotrexate);

• Transport proteins (eg, Na+,K+ ATPase, the membrane

receptor for cardioactive digitalis glycosides); and

• Structural proteins (eg, tubulin, the receptor for

colchicine, an anti-inflammatory agent).

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RECEPTOR RESERVE OR SPARE
RECEPTORS

Receptors are said to be "spare" for a given

pharmacologic response if it is possible to elicit a
maximal biologic response at a concentration of
agonist that does not result in occupancy of the full
complement of available receptors.

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SPARE RECEPTORS…

• Maximal effect does not require occupation of all

receptors by agonist.
• Low concentrations of competitive irreversible
antagonists may bind to receptors and a
maximal response can still be achieved.
• The actual number of receptors may exceed
the number of effector molecules available.

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meaning....

SPARE RECEPTORS --- are receptors that does not bind

drug when the drug concentration is sufficient to produce maximal
effect.

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Drug Mechanisms

•Receptor interactions

•Non-receptor mechanisms

107
Receptor Interactions

Lock and key mechanism

Agonist Receptor

Agonist-Receptor
Interaction
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 TYPES of DRUG-RECEPTOR
INTERACTIONS:
a. AGONIST – drugs that bind to and activate the
receptor which directly or indirectly brings about the
effect.
a.1 FULL AGONIST – drugs bind to receptors and activate
them but do not evoke as great a response

a.2 PARTIAL AGONIST – may act as either an agonist (if

no full agonist is present) or as an antagonist (if a
full agonist is present)

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Agonists and Antagonists

b. ANTAGONIST
A drug is said to be an antagonist when it binds to a
receptor and prevents (blocks or inhibits) a natural
compound or a drug to have an effect on the
receptor. An antagonist has NO
activity.

Its intrinsic activity is = 0

110
111
Drug Antagonism – one drug decrease or
inhibits action of another drug
TYPES of ANTAGONISM:
• Pharmacological
• Competitive
• Non-competitive
• Physiologic
• Chemical

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b.1 Pharmacologic antagonism:
b.1.1 Competitive antagonist
= antagonist binds with the same
receptors as the agonist.
= a pharmacologic antagonist that can be
overcome by increasing the dose of an
agonist.
= “surmountable” / reversible
= examples, Propranolol = Norepinephrine;
Morphine = Naloxone
 b.1.2 Non-competitive or Irreversible antagonist
= binds to another site of receptors.
= a pharmacologic antagonist that cannot be overcome by increasing the dose
of agonist.
= ”non-surmountable” / irreversible
= example, Phenoxybenzamine (an irreversible 𝛼 −
adrenoceptor antagonist)

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Physiologic Antagonism

b.2 Physiologic ANTAGONIST

• A drug that binds to a different receptor, and antagonize action
of each other.

• Examples:
• antagonism of the bronchoconstrictor action of HISTAMINE (mediated
@ histamine receptors) by EPINEPHRINE`S bronchodilator action
(mediated @ beta adrenoceptors)

- Glucocorticoid Hormones  Blood Sugar

Insulin  Blood Sugar

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b.3 Chemical antagonism
=a type of antagonism where a drug counters the
effects of another by simple chemical reaction /
neutralization (not binding to the receptor)
= examples:
1. Calcium sodium edetate form insoluble complexes
with arsenic / lead

2. Heparin, an anticoagulant, acidic

If there is too much  bleeding and hemorrhaging
Protamine sulfate is a base. It forms a stable
inactive complex with heparin and inactivates it.
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SECOND MESSENGERS:

• are molecules that relay signals received at receptors on the cell

surface — such as the arrival of protein hormones, growth factors,
etc. — to target molecules in the cytosol and/or nucleus.

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SECOND MESSENGERS

• But in addition to their job as relay molecules, second messengers

serve to greatly amplify the strength of the signal.
• Binding of a ligand to a single receptor at the cell surface may end up
causing massive changes in the biochemical activities within the cell.

118
119
There are 3 major classes of second
messengers:
• cyclic nucleotides (e.g., cAMP and cGMP)

• Phosphoinositides = inositol trisphosphate (IP3) and diacylglycerol (DAG)

• calcium ions (Ca2+)

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cyclic nucleotides (e.g.cAMP & cGMP)

• Acting as an intracellular second messenger.

• it mediates such hormonal responses as: a.
increased rate and contractile force of heart muscle
(β adrenomimetic catecholamines)
b. Increased cGMP concentration causes
relaxation of vascular smooth muscle by a
kinase-mediated mechanism that results in
dephosphorylation of myosin light chains

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 (PHOSPHOINOSITIDES)
inositol trisphosphate (IP3) and diacylglycerol
(DAG)
• bind to G protein-coupled receptors (GPCRs) that activate the
intracellular enzyme phospholipase C (PLC).

• Example, the therapeutic effects of LITHIUM ion, for treating manic-

depressive disorder, maybe mediated by effects on the metabolism of
phosphoinositides.

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Drug Mechanisms

•Receptor interactions

•Non-receptor mechanisms

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Non-receptor Mechanisms
1. Actions on Enzymes
• Enzymes = Biological catalysts
• Speed chemical reactions
• Are not changed themselves
• Drugs altering enzyme activity alter processes catalyzed by the enzymes
• Examples
• Cholinesterase inhibitors
• Monoamine oxidase inhibitors

124
Non-receptor Mechanisms

2. Changing Physical Properties

• Mannitol

• Changes osmotic balance across membranes

• Causes urine production (osmotic diuresis)

125
Non-receptor Mechanisms

3. Changing Cell Membrane Permeability

• Lidocaine
• Blocks sodium channels
• Verapamil, Nifedipine
• Block calcium channels

126
Non-receptor Mechanisms

4. Combining With Other Chemicals

• Antacids
• Antiseptic effects of alcohol, phenol
• Chelation of heavy metals

127
Non-receptor Mechanisms

5. Anti-metabolites
• Enter biochemical reactions in place of normal substrate “competitors”
• Result in biologically inactive product
• Examples
• Some anti-neoplastics (anti-cancer)
• Some anti-infectives (antimicrobials)

128
 Therapeutic Index

• is usually defined as the ratio of the TD50 to the ED50

for some therapeutically relevant effect.
• The range between the minimum toxic dose and the
minimum therapeutic dose – THERAPEUTIC WINDOW
• Drug’s safety margin
• Must be >1 for drug to be usable
• Examples:
• Digitalis has a TI of 2
• Penicillin has TI of >100

129
Drug-Drug Interactions

• Definition: Drug interaction -- when one drug affects the

pharmacological response of a second drug given at the same time.
• Drug interactions may be due to:
• pharmacodynamic effects
• pharmacokinetic effects

130
• Consequences of drug interactions:

• increased drug effects;

• decreased drug effects;
• desired consequences;
• adverse or undesired effects

131
• Examples -- positive, beneficial drug interaction effects:
• propranolol + hydralazine (reflex tachycardia
(undesirable) caused by hypotensive hydralazine-mediated
response is prevented by propranolol-mediated b-adrenergic
receptor blockade

• Opioid-induced respiratory depression may be

counteracted by administration of the opioid
receptor antagonist naloxone

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• Adverse effects -- toxic reactions
• one drug may interact with another to
impede absorption
• one drug may compete with another for the
same plasma protein-binding sites
• one drug may affect metabolism of another
by either enzyme induction or enzyme
inhibition
• one drug may change the renal excretion
rate of the other.

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DRUG-DRUG INTERACTIONS
T ricyclic antidepressants
H2 antagonist ( Tagamet )
E thanol
rythromycin

M AO inhibitors
A minophylline
D igoxin, Dilantin, Diuretics

W arfarin
A zole ( antifungal )
R ifampin
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 FOOD-DRUG INTERACTIONS
• DRUG • FOODS to AVOID
1. ANTACIDS bran and whole grain breads
(Ca carbonate)

2. ANTIBIOTICS citrus fruits, colas

(erythromycin, PCN)

3. TETRACYCLINE Ca-rich foods (milk)

4. ANTICOAGULANTS vit. K rich foods

(warfarin)

5. MAO inhibitors tyramine-rich foods

(cheese, chocolate, raisins)
 ENHANCEMENT of DRUG EFFECTS:
• ADDITIVE DRUG EFFECTS

= occur if two drugs with the same effect

when given together produce an effect
that is equal in magnitude to the sum of
the effects when the drugs are given
individually.

Ex: EAB = EA + EB 1+1=2

136
• SYNERGISM
= occurs if two drugs with the same effect, when given together,
produce an effect that is greater in magnitude than the sum of the
effects when the drugs are given individually.

Ex: EAB > EA + EB 1+1>2

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CO TRIM OXAZOLE

TRIMETHOPRIM + SULFAMETHOXAZOLE

138
• POTENTIATION

= occurs if a drug is lacking an effect of its own increases the

effect of a second, active drug.

Ex: EAB > EA + EB 0+1>1

139
Pregnancy Considerations

• Increased maternal HR, CO and blood volume

• May affect absorption, distribution, effectiveness
• Drugs may cross placenta
• Drugs may cross into breast milk
• Teratogens

140
Pregnancy Categories table 59-2

• A: controlled studies in pregnancy (<1 %).

• B: animal studies show no risk; Inadequate human data.
• C: animal studies show risk, inadequate human data.
• D: human data show risk, benefit may outweigh risk.
• X: animal or human data positive for risk. Use unwarranted.

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Drug Classification

• By chemistry
• electrolytes
• By mechanism
• Beta blockers
• benzodiazepines
• By disease
• antihypertensives
• Antiemetics

142