Transcript WS0201: Biomedical Pharmacology

WS0201:
Biomedical Pharmacology
UNIT 1- The Basics
Sources of Drugs
Pharmacognosy
Sources of Drugs
Animals
Plant
Minerals
Synthetics
Biologicals- recombinant DNA (rDNA)
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Herbs,
Animals,
Plants, and
Minerals
Herb examples:
1.
2.
3.
4.
5.
6.
7.
8.
Aspidium, (tapeworm)
Cinnamon, (antioxidant)
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Ergot, (migraine)
Hyoscyamus, henbane (sedative)
Foxglove, (Digitalis)
Belladonna (atropine)
Opium (morphine)
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Rauwolfia Serpentina (reserpine)
shégēn mù (蛇根木) or
yìndù shémù (印度蛇木).
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1
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Sources of Drugs
Plant SourcesSeeds, Roots, Leaves, Resins
Animal Sources- Glandualr productsinsulin, thyroid; Microbes
Mineral SourcesPotassium, Calcium, Lithium
SyntheticBarbiturates, Sulfonamides, Aspirin
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FACT:
Over 20 new drugs launched between
2000-2005 originated from:
plants/ animals/ microorganisms/
marine species/
Anticancer drugs- campothecin,
paclitaxel, epipodophyllotoxin,
vinblastine
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? DRUGS
Drugs are chemicals used
to diagnose, treat and
prevent disease.
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? Pharmacology
The study of drugs and their
actions on the body.
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Medication Names
Chemical Name:
Ethyl-1-methyl-4-phenylisonipecotate hydrochloride
Generic Name:
Meperidine hydrochloride
Trade Name:
Demerol
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Drug References
Physician’s Desk Reference
Drug Inserts
Pharmacy
Physician
Internet
USP- the only legally recognized source
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Drug Forms
Solution = Dissolved in water
Suspension = mixed in water shake before use
Elixir = mixed in alcohol
Syrup = mixed in sugar water
Tablet = firmly compressed pieces
Capsule = encased in gelatin shell
Suppository = solidified in glycerin or wax, to melt
at body temperature
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Terminology of
Pharmacology
Indication
Contraindication
Agonism
Antagonism
Additive effect
Synergistic effect
Tolerance
Habituation
Hypersensitivity
Refractory
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Terminology of
Pharmacology
Side Effects
Therapeutic Action
Untoward Effect (Adverse Effects)
Anaphylaxis
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Medication History
Clue to medical conditions
Safeguard against interactions
Safeguard against allergic reactions
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Special Considerations
Age
Allergies
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Implanted Port
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Peripherally Inserted Central
Catheter (PICC)
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FDA LAWS
The first drug law of the land
1906
The original Food and Drugs Act is passed by
Congress on June 30 and signed by President
Theodore Roosevelt.
It prohibits interstate commerce in misbranded
and adulterated foods, drinks and drugs.
cure-all claims for worthless and dangerous patent
medicines were the major problems leading to the
enactment of these laws.
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1914
The Harrison Narcotic Act requires prescriptions
for products exceeding the allowable limit of
narcotics and mandates increased record-keeping
for physicians and pharmacists who dispense
narcotics.
First time the word narcotic introduced into the
vocabulary
Narcos (Greek)= sleep
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1938
The Federal Food, Drug, and Cosmetic (FDC) Act
of 1938 provisions:
Extending control to cosmetics and therapeutic
devices.
Requiring new drugs to be shown safe before
marketing-starting a new system of drug
regulation.
Providing that safe tolerances be set for
unavoidable poisonous substances.
Authorizing standards of identity, quality, and fill
of-container for foods.
Authorizing factory inspections.
Adding the remedy of court injunctions to the
previous penalties of seizures and prosecutions.
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1951
Durham-Humphrey Amendment defines the kinds of drugs
that cannot be safely used without medical supervision and
restricts their sale to prescription by a licensed practitioner.
Birth of the legend:
‘Not to be sold without a prescription’
Defined the new category of OTC drugs
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1962
Thalidomide, a new sleeping pill, is found to
have caused birth defects in thousands of babies
born in western Europe.
Kefauver-Harris Drug Amendments passed to
ensure drug efficacy and greater drug safety. For
the first time, drug manufacturers are required to
prove to FDA the effectiveness of their products
before marketing them.
Consumer Bill of Rights is proclaimed by
President John F. Kennedy in a message to
Congress. Included are the right to safety, the right
to be informed, the right to choose, and the right to
be heard.
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1970
The Comprehensive Drug Abuse
Prevention and Control Act replaces
previous laws and categorizes drugs based
on abuse and addiction potential compared
to their therapeutic value.
DEA and DOJ responsible of administering
the act
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CSA Schedules
Schedule I-LSD; Cannabis; Heroin, MDMA=
methylene-dioxy-meth-amphetamine (Ecstasy)
Schedule II- Cocaine; Morphine; Methylphenidate
(Ritalin); Oxycontin, Vicodin;
Schedule III -Opioid derivatives, Anabolic steroids,
Hydrocodone
Schedule IV-Sedatives/ Tranquilizers- Barbiturates,
Benzo- Valium (Diazepam), Xanax (Alprazolam);
Ambien (Zolpidem); Phenobarb
Schedule V-Found in OTC drugs – loperamide,
robatussin AC
Refer Table 1-2 on Page 9
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1983
Orphan Drug Act passed, enabling
FDA to promote research and
marketing of drugs needed for treating
rare diseases.
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1994: DSHEA
Dietary Supplement Health and Education Act establishes
specific labeling requirements, provides a regulatory
framework, and authorizes FDA to promulgate good
manufacturing practice regulations for dietary supplements.
This act defines "dietary supplements" and "dietary
ingredients" and classifies them as food. The act also
establishes a commission to recommend how to regulate
claims.
Important for TCM herbalists
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Public Health Security and Bioterrorism
Preparedness and Response Act of 2002
designed to improve the country's ability to prevent and respond to public health
emergencies, and
provisions include a requirement that FDA issue
regulations to enhance controls over imported and
domestically produced commodities it regulates.
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2004 Project BioShield Act
Authorizes FDA to expedite its review
procedures to enable rapid distribution of
treatments as countermeasures to chemical,
biological, and nuclear agents that may be
used in a terrorist attack against the U. S.,
among other provisions.
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FDA Pregnancy Categories
Category
Risk Level
A
No risk
B
Risk cannot be ruled out
C
Caution is advised
D
Is a definite risk
X
Do not use
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Pre-clinical
YEARS 3.5
Patient
Numbers
Purpose:
Biological
Activity and
safety
Phase I Phase II
1-2
2.0
20-80
100-300
Phase III
3.5
FDA
2.5
1000-15000
Long term use
Safety and Effectiveness
Effectiveness
dosage
And safety
Adverse reactions
Phase IV
Total time= 12 years minimum
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Preclinical
Synthesis
and
Purification
Clinical Studies
NDA Review
New Drug Application
Phase I
Phase II
Phase III
Animal
Testing
Accelerated Development
Investigational New Drug Application
INDA Submitted
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Approval
Research pharmaceutical companies invested
$12.6 billion in R&D in 2001
Average cost per successful drug is between
$100-$300 million
1 chance in 5000 from bench top
1 chance in five through clinical trials
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Approval
Rituximab – an anti-cancer antibody against nonHodgkin’s lymphoma grossed $1.3 billion in the
first 18 months
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Drug Receptors
Binding
Signal Transduction
Receptor?
*GFP-green
fluroscent
protein
‘SEMscanning
electon
micrography
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Major Classes of Receptors
Ligand-Gated Ion
Channels
Tyrosine KinaseLinked Receptors
G-Protein Coupled
Receptors
Ligand-Activated
Transcription Factors
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Intracellular receptors
•Some are proteins located in the cytoplasm or
nucleus of target cells.
•• The signal molecule must be able to pass through
plasma membrane.
•Examples:
• ~Nitric oxide (NO)
• ~Steroid (e.g., estradiol, progesterone,
testosterone)
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B. Second Messengers
•Small, nonprotein, water-soluble molecules or ions
•Readily spread throughout the cell by diffusion
•Two most widely used second messengers are:
1. Cycle AMP (cAMP)
2. Calcium ions Ca2+
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HOW DRUGS WORK?
Most drugs work by interacting with
endogenous proteins:
• Some drugs
1 antagonize, block or inhibit endogenous proteins
• Some drugs
2 activate endogenous proteins
• A few drugs have
3 unconventional mechanisms of action
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DRUGS THAT
ANTAGONIZE, BLOCK OR INHIBIT
ENDOGENOUS PROTEINS
 Antagonists of Cell Surface Receptors
 Antagonists of Nuclear Receptors
 Enzyme Inhibitors
 Ion Channel Blockers
 Transport Inhibitors
 Inhibitors of Signal Transduction Proteins
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Absorption Distribution
Metabolism Excretion
Some Definitions!
Pharmacodynamics: is the study of what a
drug does to the body, whereas
Pharmacokinetics: is the study of what the
body does to a drug.
Definitions: Table 1:1 page 3
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Pharmacokinetics
study of the chemical alterations a drug may
undergo in the body, ("biotransformation"), and
study of the means by which drugs are stored in
the body and eliminated from it.
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Bioavailability:
The percent of dose entering the systemic
circulation after administration of a given dosage
form.
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First Pass Effect:
The biotransformation and/or excretion of a drug
by intestinal and hepatic, including biliary,
mechanisms following absorption of the drug
from the gastrointestinal tract, before drug
gains access to the systemic circulation.
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Potency:
An expression of the activity of a drug, in terms of
the concentration or amount needed to produce a
defined effect; an imprecise term that should
always be further defined
Refer Dose response curve Data Page 6
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The "half-life" of a drug; the amount of time required for
the concentration of a drug in, e.g., a body fluid such as
plasma, serum, or blood, to be halved.
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WHY DRUGS?
Ultimate goal of pharmacologic therapeutics:
“to achieve a desired beneficial effect with minimal adverse
effects”
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Routes of Administration
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Routes of Drug Delivery
Parenteral
(IV)
Inhaled
Oral
Transdermal
Parenteral
(SC, IM)
Topical
Rectal
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Bioavailability- amount
of drug available in the
blood stream
Destroyed
in gut
Dose
Not
absorbed
Destroyed
by gut wall
Destroyed
by liver
to
systemic
circulation
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Body fluid compartments
Only free drug
molecules can
cross the fluid
compartments
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The life and times
of a
drug!
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Drug Absorption
 Process by which a drug moves from site of
administration to blood or site of action
 Requires passage across biological membranes
 Mostly by passive diffusion
 Sometimes by active transportation
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Physiological Factors Affecting Oral Drug
Absorption
 GI Motility1.if decreased delays drug absorption
2.can be decreased by drugs/ food/ disease
 GI Blood flow
 Surface Area Small Intestine surgery
 Metabolism and efflux- small intestinal
lymphatics
 Changes in pH affects polarity of drug
pH can be altered by food/ disease/ other drugs
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Drug Absorption : Summary
 Most drugs absorbed by passive diffusion
 Lipid soluble drugs are more readily
absorbed than non lipid soluble drugs
 Non-ionized drugs are more readily
absorbed than ionized ones
 Weak acids /Weak bases are more readily
absorbed than strong acids/bases
 Most drugs are absorbed in the
small intestine
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?BIOAVAILABILITY
 The amount of administered drug that reaches the
systemic circulation following administration by any
route:
IV = 100%
Oral = Less than 100%
Other routes = ~ 100%
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Drug Distribution: Issues
 Drug AffinityBones/ TeethTetracycline has high affinity for calcium
Thyroid- Iodine containing drugs
Adipose tissueCan accumulate lipid soluble drugs
 Blood brain barrier; placental barrier inhibits
certain drugs from reaching the brain/ fetus
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Distribution- Plasma Protein
Binding
Refer Data on Page 19
 Many drugs bind reversibly with proteins in blood and
tissues
 Binding to serum albumin is the common method:
Albumin bound drugs are not ‘available’
Albumin bound drugs can act as a reservoir
 Amount of ‘free’ drug can be increased by
Displacement by another drug
Decreased albumin levels due to disease
Very important for drugs which are highly protein
binding- like Coumadin (Warfarin)
Also forms the basis of some of the herb/drug interactions
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Refer Data on Page 20-21
Elimination
of
Drugs
 Drugs work only for a finite length of time
 The duration of the drug action is determined by
biotransformation and excretion
(elimination process)
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Cytochrome P450: CYP450
 Metabolize 50-70% of drugs
 Inhibitors- Antifungals; Antibiotics;
Diet (grapefruit juice)
 Inducers- Anticonvulsants/ Steroids/
HIV drugs/ Antibiotics
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Ethnic variation!
The rate of metabolism can vary
up to 50 fold within the population
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Sites of Drug Excretion
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Kidney
Liver
Other – Sweat/ Tears/ Milk/ Lung
Refer Data on Page 20-21
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LD 50 & ED 50
LD 50- Lethal Dose of a drug required to kill at
least 50% of the animals tested
ED 50- Effective Dose of a drug required to
achieve therapeutic levels in at least 50% of
animals tested
Toxic Dose
Refer Data on Page 7
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Therapeutic Index:
TI
A number ratio , LD50/ED50, which is a measure
of the approximate "safety factor" for a drug; a
drug with a high index can presumably be
administered with greater safety than one with a
low index (ratio 1~ or less than 1).
In case of humans it is Toxic dose
divided by (therapeutic) effective dose
(TD50/ED50)
Refer Data on Page 7
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BIOMEDICAL
PHARMACOLOGY:
WS0201
ABSORPTION : Q&A
WHAT IS DRUG ABSORPTION?
The movement of drug molecules across
biological barriers (mostly layers of cells) from
the site of administration to the blood stream.
Site of Administration
Vascular System
DRUG
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WHY BE CONCERNED ABOUT
DRUG ABSORPTION?
This issue importantly affects:
• Bioavailability - % of dose that gets into body
• Bioequivalence - similarity between two formulations of
same drug
• Speed of Drug Onset - how long it takes the drug to
begin working
• Dosing Interval - how often the drug should be given
• Site of Action - whether the drug stays local or acts
systemically
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WHAT AFFECTS DRUG ABSORPTION?
The rate of drug absorption will be affected by:
• Rate of release of drug from pharmaceutical preparation
• Membrane permeability of drug
• Surface area in contact with drug
• Blood flow to site of absorption
• Destruction of drug at or near site of absorption
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WHAT DETERMINES RATE OF
RELEASE OF DRUG FROM
PHARMACEUTICAL
PREPARATION?
A: DOSAGE FORM
•
• Solutions: No Delay, Immediate Release
• Capsules & Tables: Delay (Dissolution)
Followed by Rapid Release
• Creams, Ointments & Suppositories: No Delay,
but Slow Release
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WHAT DETERMINES RATE OF
RELEASE OF DRUG FROM
PHARMACEUTICAL
PREPARATION?
B: ADDITIVES (EXCIPIENTS)
Decrease Rate of
Dissolution
Increase Rate of
Dissolution
Variable Effects on
Rate of Dissolution
• Binders
• Lubricants
• Coating Agents
• Disintegrants
• Diluents
• Coloring Agents
• Flavoring Agents
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WHAT DETERMINES RATE OF
RELEASE OF DRUG FROM
PHARMACEUTICAL
PREPARTAION?
C: MANUFACTURING PARAMETERS
•
•Tablet Compression - Hard tablets dissolve more slowly
• Tablet Shape - Round tablets dissolve more slowly
•Tablet Size - Large tablets dissolve more slowly
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WHAT DETERMINES RATE OF
RELEASE OF DRUG FROM
PHARMACEUTICAL
PREPARATION?
D: DELAYED RELEASE PREPARATIONS
• Enteric Coating - Dissolve in intestines, not stomach
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WHAT DETERMINES MEMBRANE
PERMEABILITY OF DRUGS?
A: LIPOPHILICITY increases membrane
permeability
• Presence of Aliphatic and Aromatic Structures
•Absence of Polar (water soluble) Groups
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WHAT DETERMINES MEMBRANE
PERMEABILITY OF DRUGS?
B: IONIZATION decreases membrane
permeability
• Weak acids in intestines are mostly ionized
(intestinal pH ranges from 6.6 to 7.5)
• Weak bases in stomach are mostly ionized
(stomach pH ranges from 1 to 2)
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WHAT DETERMINES SURFACE
AREA FOR ABSORPTION?
ANATOMY
• Low Surface Area:
eyes, nasal cavity, buccal cavity,
rectum, stomach, large intestines
• High Surface Area: small intestines, lungs
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WHAT DETERMINES
TISSUE BLOOD FLOW?
A. PHYSIOLOGY
• Low Blood Flow:
eyes, stomach, large intestines,
rectum, subcutaneous tissue
• High Blood Flow
small intestines, lungs, muscle, buccal cavity, nasal cavity
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WHAT DETERMINES
TISSUE BLOOD FLOW?
B. PHARMACOLOGY
• Some Drugs Are Vasoconstrictors
• Some Drugs Are Co-Administered With Vasoconstrictors
•Some Drugs Are Vasodilators
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WHAT DETERMINES
WHETHER A DRUG IS DESTROYED
AT OR NEAR SITE OF ADMINISTRATION?
BIOCHEMISTRY
• Liver - hepatic enzymes (“first pass” effect)
• Colon - intestinal microflora
•Stomach - digestive enzymes and acids
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WHAT ARE THE ROUTES OF
ADMINISTRATION FOR DRUGS?
ENTERAL
• Intravenous (IV)
•
• Intra-arterial (IA)
•Oral
• Subcutaneous (SC)
• Intradermal (ID)
•Sublingual
• Intramuscular (IM)
• Intraperitoneal (IP)
•Rectal
• Lungs (Inhalation)
• Skin (Topical)
PARENTERAL
•Nose (Intranasal)
• Eye (Opthalmic)
• Ear (Otic)
• Vagina
• Urethra
• Urinary Bladder
• Intrathecal
• Epidural
• Directly Into Target Tissue
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WHAT ARE THE ADVANTAGES AND DISADVANTAGES OF
ORAL, IV, IM AND SC ADMINISTRATION?
SAFETY
High
Oral > SC > IM > IV
Low
CONVENIENCE
High
Oral > SC > IM > IV
Low
COST
High
IV > IM > SC > ORAL
Low
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WHAT ARE THE ADVANTAGES AND DISADVANTAGES OF
ORAL, IV, IM AND SC ADMINISTRATION?
BIOAVAILABILITY
High and Reliable
IV > IM = SC > ORAL Low and/or Variable
ONSET OF ACTION
Immediate
IV > IM > SC > Oral
Delayed
PATIENT COMPLIANCE
High
IV > IM > SC > Oral
Low
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WHAT ARE THE ADVANTAGES AND DISADVANTAGES OF
ORAL, IV, IM AND SC ADMINISTRATION?
INTERACTIONS WITH FOOD
Risk
Oral > IV = IM = SC
No Risk
COMMERCIAL AVAILABILITY OF DOSAGE FORMS
High
Oral > IM = SC = IV
Low
VOLUME OF DRUG
High
Oral = IV > IM > SC
Low
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WHAT ARE THE ADVANTAGES AND DISADVANTAGES OF
ORAL, IV, IM AND SC ADMINISTRATION?
AVAILABILITY OF SUSTAINED RELEASE
DOSAGE FORMS
High
IM > Oral > SC > IV
Low
POSSIBLE VEHICLES FOR ADMINISTERING DRUG
High
Oral = IM = SC > IV
Low
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WHY CONSIDER OTHER ROUTES OF
ADMINISTRATION?
•
•Sublingual - Rapid absorption that bypasses liver
• Rectal - Great for patient that is vomiting or
cannot (will not) swallow medication;
also partially (50%) bypasses liver
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WHY CONSIDER OTHER ROUTES OF
ADMINISTRATION?
IS OFTEN DESIRABLE TO CONCENTRATE
MEDICATION AT TARGET SITE TO
INCREASE EFFICACY AND
DECREASE TOXICITY
• Lungs (Inhalation)
• Skin (Topical)
• Nose (Intranasal)
• Eye (Opthalmic)
• Ear (Otic)
• Vagina
• Urethra
• Urinary Bladder
• Intrathecal
• Epidural
• Directly Into Target Tissue
(The purpose here is to limit systemic absorption)
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