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Pharmacology

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Why Do We Study Pharmacology?

• A. It’s good for you


• B. You will be able to use fancy terms like
’bioavailabilty’
• C. My instructor likes to torture people
• D. A competent nurse must understand why
his/her patient is getting a medication, and
HOW IT WORKS

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Purpose of Drug Therapy

• “… to prevent, control or cure various disease


states.”
• To achieve this, the right drug dose must be
delivered to the tissues
• Every nurse must know…
– speed of onset of drug action
– intensity of drug effect
– duration of drug action
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A Graphical Example:
Drug Concentration

Lethal
Dose

Peak Onset


Therapeutic
Range
Duration
Sub-
Therapeutic

Time in Hours
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How Do We Study
Pharmacology?

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General Concepts
Drug Dose
Administration

Disintegration
Pharmaceutical
of Drug

Absorption/distributio
Pharmacokinetics
n
metabolism/excretion
Drug/Receptor
Pharmacodynamics Interaction
Drug Effect
Pharmacotherapeutics
or Response

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How are Drugs
Administered?

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Routes of Drug Delivery
Parenteral Inhaled
(IV)
Oral

Transdermal
Parenteral
Topical (SC, IM)

Rectal
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What Happens After Drug
Administration?
Drug at site
of administration
1. Absorption
Drug in plasma 2. Distribution
Drug/metabolites
3. Metabolism
in tissues

4. Elimination
Drug/metabolites
in urine, feces, bile
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Modified from Mycek et al. (1997)
We are now talking about …

Pharmacokinetics

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Factors Affecting Drug Absorption
ATP
• Transport
– active vs. passive
• pH ADP
+ Pi
• Physical factors
– blood flow
– surface area A-
– contact time BH+

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What Factors Affect Distribution?
Endothelial cells
• Blood flow in liver capillary
– brain vs. fat
• Capillary permeability
– differences in
capillary structure
• Binding to proteins
– role of albumin
Endothelial cells
in brain capillary Glial cell
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An Important Concept:
BIOAVAILABIITY
• Def’n:
– Fraction of a drug that reaches

Serum Concentration
systemic circulation after a
particular route of admin’n

• Affected by: Injected Dose


– 1st pass metabolism (eg:
Lidocaine, propranolol)
– Solubility
– Instability (eg:
Penicillin G, insulin)
Oral Dose
Time
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Volume of Drug Distribution

• Drugs may distribute into Plasma


any or all of the following (4 litres)
compartments:
– Plasma Interstitial Fluid
– Interstitial Fluid (10 litres)
– Intracellular Fluid
Intracellular Fluid
(28 litres)

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So What?
• Most drugs distribute into
several compartments;
however …
• Some drugs distribute into
only one or two
compartments
• Eg: Aminoglycoside
antibiotics
– Streptomycin
– Gentamycin
Arggh! I can’t fit through these
darn fenestrations!
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More “So What?”
• It takes time for a drug to distribute in the body
• Drug distribution is affected by elimination
Serum Concentration

1.5

Drug is not eliminated


1.0 Elimination Phase

0.5
Distribution Phase Drug is eliminated
0
0 Time
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Albumin Affects Distribution
• Drugs bind differentially to Albumin
albumin
• 2 drug classifications:
– Class I: dose less than
available binding sites (eg: Drug X
most drugs)
– Class II: dose greater than
binding sites (eg:
sulfonamide)

• The problem:
– one drug may out-compete
the other

Sulfonamide
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Drug Metabolism
(we’re still talking about
Pharmacokinetics)

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Drug Metabolism

• First pass
– metabolism of drugs may occur as they cross the
intestine or transit the liver
• eg: nitroglycerin

• Other drugs may be destroyed before


absorption
• eg: penicillin

• Such reactions decrease delivery to the


target tissues
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Drug Metabolism (cont’d)
• Two Phases: I and II Drug
– Phase I: conversion Phase I
to lipophilic cpds Oxidation
– Phase II: Reduction
conjugation Hydrolysis
• Phase I involves the Activation/Inactivation
cytochrome P-450
system Phase II
• Ultimate effect is to Glucuronidation
facilitate elimination
Conjugation Products
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An Example of Phase I and II
Biotransformation:

CH3CON- -OC2H5 Phenacetin


H
PHASE I

CH3CON- -OH Paracetamol


H
PHASE II
OH
Glucuronic Acid
CH3CON- -O- HO -OH Conjugate
H (USA). All rights reserved.
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An Example of Drug Metabolism

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First Pass Metabolism Occurs
Primarily in the Liver and Gut

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Drug Elimination

• Most important route is the kidney

• May also involve bile, intestine, lung, breast


milk

• What clinical scenarios may affect drug


elimination?

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Elimination of a drug is usually linked
to renal filtration, secretion and
reabsorption.

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Food for Thought

• What conditions might affect renal function


(and therefore drug elimination)?

• What other organ systems are involved in


drug clearance?

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Important Point

• The pharmacokinetic profile of a drug also


depends on its mode of administration …

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Example: Intravenous Infusions

• Plasma
concentration rises

Plasma Concentration
until elimination =
input Fast Infusion
• Faster infusions get
more drugs on
board, but does not Slow Infusion
change the time to
achieve a steady
state
Time
Time at which
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steady state is achieved
Example: Intravenous Injection

• Peak plasma
concentration of the 100 mg injected
drug is achieved at

Plasma Concentration
time = 0
• There is no steady
state concentration. 50 mg injected
Why?

Time
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Example: Oral Dose
• A single oral dose
will give you a single
peak plasma

Plasma Concentration
concentration
• The drug
concentration then
continuously
declines
• Repeated doses
result in oscillations
in plasma
concentration Time
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Are We Having Fun Yet?

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What is Pharmacology?

From the Greek pharmakon (drug), legein (to


speak)

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• Broadly defined as the study of how
chemical agents affect living processes.
• Hormones
• Neurotransmitters
• Growth factors
• local Autocrine factors
• Drugs (Pharmaceuticals)
• Toxic agents in the environment
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• the medicinal/ organic chemist
may create the candidate
compound (sometimes referred
to as a new chemical entity,
NCE), it is the pharmacologist
who is responsible for testing it
for pharmacological activity.

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• ultimately will lead to the
discovery of novel drug targets
for therapeutic intervention in
diseases where distal steps in
signal transduction have gone
awry

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Pharmacology
• The study of how drugs exert their
effects on living systems.
Pharmacologists work to identify
drug targets in order to learn how
drugs work. Pharmacologists also
study the ways in which drugs are
modified within organisms.

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In most of the pharmacologic
specialties, drugs are also used
today as tools to gain insight
into both normal and abnormal
function.
science of drugs

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Drug

• Any chemical that affects the


processes of
a living organism

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Medical pharmacology

• is the study of drugs used for


the diagnosis, prevention, and
treatment of disease.

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Some Pharmacology
Definitions and Areas of
Study

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Pharmacotherapeutics

• use of drugs to treat disorders;


the emphasis is on clinical
management

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Pharmacoepidemiology

• study of the effect of drugs on


populations; questions dealing
with the influence of genetics
are particularly important

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Pharmacoeconomics

• study of the cost-effectiveness


of drug treatments; the cost of
medications is of worldwide
concern, particularly among
certain groups such as the
elderly and AIDS patients

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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.

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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.
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THE NATURE OF
DRUGS

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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.

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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,
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• 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), and less
commonly by covalent bonds.
• Weaker, noncovalent 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.
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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.

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• Most chiral drugs are still provided as
racemic mixtures (mixtures of
isomers) because it is expensive to
separate the stereoisomers. In the
past, little was known about the
relative activity of stereoisomers.
However, the Food and Drug
Administration (FDA) now requires
information about the structure and
activity of each isomer present in a
racemic mixture of a new medication.
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Drug Names

• Chemical name
• Generic name
• Trade name
• Official name

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Chemical Name

• Gives the exact chemical makeup of the drug


• Not capitalized
• The drug’s chemical composition and
molecular structure

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Generic Name(nonproprietary
name)

• Name given before the drug becomes official


• May be used in all countries and all
manufacturers
• Not capitalized

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Trade Name(proprietary name)

• Name can only be used by the manufacturer


• Name that is registered by the manufacturer
and followed by the trademark symbol
• A drug may have several trade names,
depending on the number of manufacturers
• Is capitalized

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Official name

• The name under which the drug is listed by


the US Food and Drug Administration (FDA).
• The FDA is empowered by federal law to
name the drugs for human use in the United
States.

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Drug Names: Examples

Chemical name
• (+/-)-2-(p-isobutylphenyl) propionic acid

Generic name
• ibuprofen

Trade name
• Motrin

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Examples

• Chemical name:4-Thia-
10azabicyclol{3.2.0}heptane-2-carboxyclic
acid,6-[2S-[2a,-5a,6B(S*)]]
• Generic name:ampicillin
• Official name:ampicillin,USP
• Brand name:Principen,Polycillin

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Pharmacologic Principles

• Pharmaceutics
• Pharmacokinetics
• Pharmacodynamics
• Pharmacotherapeutics
• Pharmacognosy

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Pharmacologic Principles

Pharmaceutics
• The study of how various drug
forms influence
pharmacokinetic and
pharmacodynamic activities

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Pharmacokinetics
Is what the body does to the drug.
The magnitude of the pharmacological effect
of a drug depends on its concentration at the
site of action.
• Absorption
• Distribution
• Metabolism
• Elimination
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Pharmacodynamics
• The study of what the drug does to the body:
– The mechanism of drug actions in living tissues

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Is what the drug does to the body.
Interaction of drugs with cellular proteins,
such as receptors or enzymes, to control
changes in physiological function of particular
organs.
• Drug-Receptor Interactions
– Binding
• Dose-Response
– Effect
• Signal Transduction
– Mechanism of action, Pathways
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Pharmacogenetics
Area of pharmacology concerned with unusual
responses to drugs caused by genetic differences
between individuals.
Responses that are not found in the general
population, such as general toxic effects, allergies, or
side effects, but due to an inherited trait that
produces a diminished or enhanced response to a
drug.
• Differences in Enzyme Activity
– Acetylation polymorphism
– Butylcholinesterase alterations
– Cytochrome P450 aberration

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Pharmacotherapeutics

• The use of drugs and the clinical indications for


drugs to prevent and treat diseases
• Study of which drug would be most or least
appropriate to use for a specific disease, what dose
would be required,etc.

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Pharmacognosy
• The study of natural (plant and animal) drug sources
• By studying the compositions of natural substances
and how the body reacts to them, one gains better
knowledge for developing synthetic versions

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Toxicology

• Study of poisons and poisonings


• As almost all drugs are capable of being toxic
effects of substances on the living organism

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Drug Category

• Prescription
• Nonprescription
• Controlled substance

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Prescription Drugs

• Designated by the federal government as


being harmful, unless their use is supervised
by a licensed health care provider
• Nurse practitioner, physician, or dentist
• Nurse monitors for harmful effects
• Largest drug category

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Rx

• Name of the drug


• Dosage
• Route
• Times of administration
• Signature

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Nonprescription Drugs

• OTC
colds, headaches, constipation, diarrhea,
upset stomach
• Safe when used as directed
• Potentially harmful
• Read the label

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Controlled Substance

• High potential for abuse


• Physical dependency
• Psychological dependency

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Pregnancy

• Both prescription and OTC can have


teratogen effects
• In general most drugs should be avoided in
pregnancy unless benefits outweight risks
• The Motherisk Program

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INTRODUCTION TO
PHARMACOKINETICS

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• Pharmacokinetics concerns the
effects of the body on the
administered drug. It can be
pictured as the processes of
absorption, distribution, and
elimination. Elimination
includes both metabolism and
excretion.

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Drug Absorption of Various

Oral Preparations
Liquids, elixirs, syrups Fastest
Suspension solutions 
Powders 
Capsules 
Tablets 
Coated tablets 
Enteric-coated tablets Slowest

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Absorption of Drugs.

• Drugs usually enter the body at sites remote


from the target tissue and are carried by the
circulation to the intended site of action.
Before a drug can enter the bloodstream, it
must be absorbed from its site of
administration. The rate and efficiency of
absorption differs depending on the route of
administration. Common routes of
administration of drugs and some of their
features include:

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Pharmacokinetics: Absorption

• The rate at which a drug leaves its site of


administration, and the extent to which
absorption occurs.
– Bioavailability
– Bioequivalent

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Pharmacokinetics: Absorption
Factors That Affect Absorption
• Administration route of the drug
• Food or fluids administered with the drug
• Dosage formulation
• Status of the absorptive surface
• Rate of blood flow to the small intestine
• Acidity of the stomach
• Status of GI motility
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Pharmacokinetics: Absorption

Routes
• A drug’s route of administration affects the rate
and extent of absorption of that drug.
– Enteral
– Parenteral
– Topical

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Pharmacokinetics: Absorption
Enteral Route
• Drug is absorbed into the systemic circulation
through the oral or gastric mucosa, the small
intestine, or rectum.
– Oral
– Sublingual
– Buccal
– Rectal

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Enteral Drug Absorption

Generally a passive process, fueled by a


concentration gradient transporting drugs
from the gut into the portal circulation

Significant types of pre-systemic clearance:


• Intestinal and hepatic metabolism
i.e., via cytochrome P450 (CYP) enzymes
• Active transport via P-glycoprotein
• Resulting “first-pass effect”

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GI drug absorption and pre-systemic metabolism

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First-Pass Effect
The metabolism of a drug and its passage
from the liver into the circulation.
• A drug given via the oral route may be
extensively metabolized by the liver before
reaching the systemic circulation (high
first-pass effect).
• The same drug—given IV—bypasses the
liver, preventing the first-pass effect from
taking place, and more drug reaches the
circulation.
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Oral/Enteral Drug Administration

Advantages:
• Avoids hazards of IV lines, infections, phlebitis
• Facilitates earlier ICU discharge (example -
enteral methadone instead of fentanyl infusion)
• Lowers drug acquisition costs by an average of
8-fold

• Caution! Drug bioavailability in critical


illness may be deranged.

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Oral/Enteral Drug Administration Should Be
Avoided in Those With…
• Ileus, no active bowel sounds

• Ischemic bowel

• Gastric residuals

• Nausea and vomiting

• Malabsorption syndrome

• Questionable gut perfusion and poor hemodynamics

• Interacting substances in gut

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Interacting GI Substances May Interfere with
Absorption

• Examples: Phenytoin, quinolones,


tetracyclines
• Enteral nutrition with enteral phenytoin often
lowers serum levels by as much as 80%.
- Many patients require intravenous phenytoin to
maintain adequate serum levels.
• Bi- and trivalent cations bind to quinolone and
tetracycline antibiotics, potentially leading to
treatment failures.
- Avoid concurrent administration of substances such as
iron, aluminum (sucralfate), magnesium, etc.
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First-Pass Effect

• Routes that bypass the liver:


– Sublingual Transdermal
– Buccal Vaginal
– Rectal* Intramuscular
– Intravenous Subcutaneous
– Intranasal Inhalation
*Rectal route undergoes a higher degree of first-
pass effects than the other routes listed.

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Pharmacokinetics: Absorption
Parenteral Route
• Intravenous*
• Intramuscular
• Subcutaneous
• Intradermal
• Intrathecal
• Intraarticular
*Fastest delivery into the blood circulation
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Pharmacokinetics: Absorption
Topical Route
• Skin (including transdermal patches)
• Eyes
• Ears
• Nose
• Lungs (inhalation)
• Vagina

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Oral (swallowed)

• Maximum convenience but may be slower


and less complete than parenteral (non-oral)
routes. Dissolution of solid formulations (eg,
tablets) must occur first. The drug must
survive exposure to stomach acid. This route
of administration is subject to the first pass
effect (metabolism of a significant amount of
drug in the gut wall and the liver, before it
reaches the systemic circulation).

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Sublingual (under the tongue)

• Permits direct absorption into the systemic


venous circulation thus avoiding the first pass
effect. May be fast or slow depending on the
physical formulation of the product.
Nitroglycerin is administered by this route in
the treatment of angina.

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Rectal (suppository).

• Same advantage as sublingual route; larger


amounts are feasible. Useful for patients who
cannot take oral medications (eg, because of
nausea and vomiting).

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Intramuscular

• Absorption is sometimes faster and more


complete than after oral administration. Large
volumes (eg, 5 - 10 mL) may be given.
Requires an injection. Generally more painful
than subcutaneous injection. Vaccines are
usually administered by this route.

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Subcutaneous

• Slower absorption than intramuscular. Large


volumes are not feasible. Requires an
injection. Insulin is administered by this route.

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Inhalation
» For respiratory diseases, this route deposits drug close to the target organ;
when used for systemic administration (e.g., nicotine Susan Masters, PhD 63

• in cigarettes, inhaled general anesthetics) it


provides rapid absorption because of the
large surface area available in the lungs.

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Topical

• Application to the skin or mucous membrane


of the nose, throat, airway, or vagina for a
local effect. It is important to note that topical
drug administration can result in significant
absorption of drug into the systemic
circulation. Drugs used to treat asthma are
usually administered this way.

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Transdermal

• application to the skin for systemic effect.


Transdermal preparations generally are
patches that stick to the skin and are worn for
a number of hours or even days. To be
effective by the transdermal route, drugs
need to be quite lipophilic. Nicotine is
available as a transdermal patch for those
who are trying to stop cigarette smoking.

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Intravenous

• Instantaneous and complete absorption (by


definition, 100%); potentially more dangerous
because the systemic circulation is transiently
exposed to high drug concentrations.

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Distribution of Drugs

• The distribution of drugs from the site of


absorption, through the bloodstream and to
the target tissue depends upon:

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• The blood flow to the tissue is important in
the rate of uptake of a drug. Tissues that
receive a high degree of blood flow (eg,
brain, kidney) have a fast rate of uptake
whereas tissues with a low degree of blood
flow (eg, adipose tissue) accumulate drug
more slowly.

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• Solubility of the drug in the tissue. Some
tissues, eg, brain, have a high lipid content
and dissolve a higher concentration of
lipophilic agents.
• Binding of the drug to macromolecules in the
blood or tissue limits their distribution.

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• The ability to cross special barriers. Many
drugs are poorly distributed to the brain and
the testis because these tissues contain
specialized capillaries (the smallest type of
blood vessel). The endothelial cells that line
these capillaries form a blood-brain barrier
and a blood-testis barrier by preventing the
movement of hydrophilic molecules out of the
blood and into the tissue, and by actively
pumping lipophilic molecules out of the
endothelial cell and into the blood.

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

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Pharmacokinetics: Metabolism
(also known as 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

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Pharmacokinetics: Metabolism

Factors that decrease metabolism:


• Cardiovascular dysfunction
• Renal insufficiency
• Starvation
• Obstructive jaundice
• Slow acetylator
• Erythromycin or ketoconazole drug therapy

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Pharmacokinetics: Metabolism

Factors that increase metabolism:


• Fast acetylator
• Barbiturates
• Rifampin therapy

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Pharmacokinetics: Metabolism

Delayed drug metabolism results in:


• Accumulation of drugs
• Prolonged action of the effects of the drugs

Stimulating drug metabolism causes:


• Diminished pharmacologic effects

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Pharmacokinetics: Excretion

The elimination of drugs from the body


• Kidneys (main organ)
• Liver
• Bowel
– Biliary excretion
– Enterohepatic circulation

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Pharmacokinetics

Half-Life
• The time it takes for one half of the original amount
of a drug in the body to be removed.
• A measure of the rate at which drugs are removed
from the body.

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Pharmacodynamics

Drug actions:
• The cellular processes involved in the drug and
cell interaction

Drug effect:
• The physiologic reaction of the body to the drug

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Pharmacodynamics
Onset
• The time it takes for the drug to elicit a
therapeutic response

Peak
• The time it takes for a drug to reach its maximum
therapeutic response

Duration
• The time a drug concentration is sufficient to elicit
a therapeutic response
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Pharmacodynamics:
Mechanisms of Action
The ways by which drugs can produce
therapeutic effects:
• Once the drug is at the site of action, it can modify
the rate (increase or decrease) at which the cells or
tissues function.
• A drug cannot make a cell or tissue perform a
function it was not designed to perform.

Copyright © 2002, 1998, Elsevier Science (USA). All rights reserved.


Pharmacodynamics:
Mechanisms of Action
• Receptor interaction
• Enzyme interaction
• Nonspecific interactions

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Pharmacotherapeutics:
Types of Therapies
• Acute therapy
• Maintenance therapy
• Supplemental therapy
• Palliative therapy
• Supportive therapy
• Prophylactic therapy

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Pharmacotherapeutics: Monitoring

• The effectiveness of the drug therapy must


be evaluated.
• One must be familiar with the drug’s
• intended therapeutic action (beneficial)
• and the drug’s unintended but potential side
effects (predictable, adverse drug reactions).

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Pharmacotherapeutics: Monitoring

• Therapeutic index
• Drug concentration
• Patient’s condition
• Tolerance and dependence
• Interactions
• Side effects/adverse drug effects

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Pharmacotherapeutics: Monitoring

Therapeutic Index
• The ratio between a drug’s therapeutic benefits
and its toxic effects

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Pharmacotherapeutics: Monitoring

Tolerance
• A decreasing response to repetitive drug doses

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Pharmacotherapeutics: Monitoring

Dependence
• A physiologic or psychological need for a drug

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Pharmacotherapeutics: Monitoring

Interactions may occur with other drugs or food


• Drug interactions: the alteration of action of
a drug by:
– Other prescribed drugs
– Over-the-counter medications
– Herbal therapies

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Pharmacotherapeutics: Monitoring

Interactions
• Additive effect
• Synergistic effect
• Antagonistic effect
• Incompatibility

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Pharmacotherapeutics: Monitoring
Medication Misadventures

Adverse drug events


• ALL are preventable
• Medication errors that result in patient harm

Adverse drug reactions


• Inherent, not preventable event occurring in the
normal therapeutic use of a drug
• Any reaction that is unexpected, undesirable, and
occurs at doses normally used
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Pharmacotherapeutics: Monitoring

Some adverse drug reactions are classified as


side effects.
• Expected, well-known reactions that result in little
or no change in patient management
• Predictable frequency
• The effect’s intensity and occurrence is related to
the size of the dose

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Pharmacotherapeutics: Monitoring

Adverse Drug Reaction

An undesirable response to drug therapy


• Idiosyncratic
• Hypersensitivity reactions
• Drug interactions

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Pharmacotherapeutics: Monitoring

Iatrogenic Responses

Unintentional adverse effects that are


treatment-induced
• Dermatologic
• Renal damage
• Blood dyscrasias
• Hepatic toxicity

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Pharmacotherapeutics: Monitoring

Other Drug-Related Effects


• Teratogenic
• Mutagenic
• Carcinogenic

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