ROUTES OF ADMINISTRATION BASIC CONCEPTS IN DRUG THERAPY

1. Alimentary/Enteral A. Dose Response Curve and Maximal

2. Non-alimentary/Parenteral Efficacy
 Threshold Dosage
FIRST-PASS EFFECT:  Plateau – indicates that there will be no
After absorption from the alimentary canal, the further increment in the response even
drug is transported directly to the liver via the if the dosage continues to be increased
portal vein, where a significant amount of the B. Potency
drug may be metabolized and destroyed prior to  Related to the dosage that produces a
reaching its site of action. given response in a specific amplitude
 Refers to the fact that less of the
ENTERAL ROUTE compound is required to produce a
ROUTE ADVANTAGE DISADVANTAGE EXAMPLE given response
ORAL Easy, safe & Limited or Drug
convenient erratic analgesics,
absorption sedative ELEMENTS OF DRUG SAFETY
First pass effect A. Quantal Dose Response Curve
SUBLINGU Rapid onset Must be easily Nitroglycerin - the percentage of the population who
AL absorbed from
oral mucosa
exhibit a specific response as the dose
(-) First pass is increased
effect B. Median Effective Dose (ED 50)
RECTAL Alternative Poor or Laxatives - Dose at which 50% of the population
to oral incomplete
respond to the drug in a specified
absorption
Local effect manner
on rectal Median Toxic Dose (TD 50)
tissue - Dosage at which 50% of the group
exhibits the adverse effect
Median Lethal Dose (LD 50)
PARENTERAL ROUTE - Dose that causes death in 50% of the
ROUTE ADVANTAGE DISADVANTAGE EXAMPLE
INHALATIO Rapid onset Chance of tissue Gen
animals studied
N irritation anesthesia C. Therapeutic Index
Direct Pt’s compliance Antiasthm - Used as an indicator of the drug’s
sometimes a atic drug safety; relates the dose of a drug
problem
INJECTION Rapid onset Chance of Insulin
required to produced a desired effect
infection if to that which produces an undesired
sterility is not effect
Direct Antibiotic TI = TD 50/ED 50
TOPICAL Local effect Only effective in Ointments
The greater the value of the TI, the
treating outer and cream
layers of skin safer the drug is and also a large TI
TRANSDER Introduces Able to pass Nitroglyce indicated that it takes much larger
MAL drug into the dermal layer of rin dose to evoke a toxic response than it
body without skin
does to cause a beneficial effect
invasion

DRUG ABSORPTION/DISTRIBUTION
VARIANTS OF INJECTION
A. Bioavailability
 Intravenous
- A parameter expressed in percentage
 Intra-arterial
of the drug administered that reaches
 Intramuscular
the bloodstream
 Subcutaneous
- Depends on the route of
 Intrathecal
administration as well as the drug’s
availability to cross the membrane
barriers
 - Defined as the fraction of unchanged
drug reaching the systemic circulation
following administration by any route
B. Membrane Structure and Function
1. Lipids – actually phospholipids that
acts as a water barrier
2. Proteins
RATE OF DIFFUSION DEPENDS ON:
A. Magnitude of the concentration difference
B. Size of the diffusing substance
C. Distance over which diffusion occurs
D. Temperature
EFFECT OF IONIZATION ON LIPID DIFFUSION
 Drug will diffuse more rapidly through
the lipid layer if they are in NEUTRAL,
NON-IONIZED FORM
 Most drugs are weak acids or weak bases
but have a potential to be charged
depending on body fluids
Weak acid in acidic environment = neutral
(stomach)
Weak acid in basic environment = positively
charged (duodenum)
DIFFUSION TRAPPING
- Changes in lipid solubility caused by
ionization can also be important when
the body attempts to excrete a drug in
the urine
DIFFUSION BETWEEN CELL JUNCTIONS:
- Drug may diffuse across the barrier by
diffusing first into and then out of the
other side of cells comprising the
barrier
- Eg: epithelial lining of the GIT,
capillary endothelium of the brain
OSMOSIS
- Refers to the special case of diffusion
where the diffusing substance is water
- Contain drugs may simply travel with
the diffusing water through the
process of “bulk flow”
ACTIVE TRANSPORT OR CARRIER-MEDIATED
TRANSPORT
- Membrane proteins shuttle
substances from one side of the
membrane to the other
- Characteristics:
 Carrier specificity
 Energy expenditure
 Transport against concentration
gradient
- Eg: Theophylline
FACILITATED DIFFUSION
- Presence of protein carrier but no net
energy expended
- Inability to transport substances
“uphill”
- Ex: Entry of glucose into skeletal
muscle cells
ENDOCYTOSIS
- Drug is engulfed by the cell via an
invagination the cell membrane
DISTRIBUTION OF DRUGS WITHIN THE BODY
Factors:
A. Tissue permeability
- A highly lipid soluble drug can
potentially reach all the different body
compartments and every cell it
reaches
- The blood-brain barrier limits the
movement of drugs out of the
bloodstream and into the CNS tissue
B. Blood Flow
- Drugs will gain greater access to tissue
that are highly perfused
C. Binding to Plasma Proteins
- Certain drugs will form reversible
bonds to circulating proteins in the
bloodstream such as albumin
- Only the unbound or “free” drug is
able to reach the target tissue and
exert the pharmacologic effect
D. Binding to Subcellular components
- Drugs bound to specific cells are
unable to leave the cell and be
distributed through other fluid
compartments
- Eg: Quinacrime
VOLUME OF DISTRIBUTION (Vd)
- Used to estimate a drug’s distribution
by comparing the Vd with the total
amount of body water in a normal
person
- Relates the amount of drug in the
body to the concentration of drug in
blood or plasma
- Vd = amount of drug administered
Concentration of drug in plasma
DRUG STORAGE
Storage Sites
1. Adipose
- Primary storage site, remain for long
periods because of low metabolic rate
and poor blood perfusion; e.g.
thiopental and halothane
2. Bone
- Storage of some toxic agents like
heavy metals; e.g. lead and
tetracycline
3. Muscle
- Reversible bonds to intracellular
structures (proteins, nucleoproteins,
phospholipids); e.g. quinacrine
4. Organs
- Liver and kidneys (aminoglycosides –
gentamycin and streptomycin)
ADVERSE CONSEQUENCES
1. Local Damage
- e.g. aluminum may be stored in the
liver and kidney and central neurons
which is neurotoxic
2. Storage site acts as a Reservoir
- Drug may be reintroduced to the
target site long after the original dose
should have been eliminated
NEWER TECHNIQUES FOR DRUG DELIVERY
1. Controlled-release Preparations:
- Also known as timed-release or
extended-release preparations
- Designed to permit a slower and more
prolonged absorption of the drug from
the GIT
- Decreases the number of doses
needed each day and prevents large
fluctuations in the amount of drug
appearing in the plasma and
sustaining plasma levels through the
night
2. Implanted Drug Delivery Systems
- Drug reservoir is implanted surgically
within the body and drug is released
in a controlled fashion from the
implanted reservoir
BIOTRANSFORMATION
- Aldo called drug metabolism
- Refers to chemical changes that take
place in the drug following
administration
- Primary function is the termination of
the drug after it has exerted
pharmacologic effect
- Drug’s structure: Catalytic changes
due to enzymes in tissue = metabolites
(inactive or reduced pharmacologic
activity)
- Inactive or “prodrug form” os given
when metabolite has a higher level of
activity
- Occurs in minutes or hours, reducing
chance for toxic effects caused by drug
accumulation or prolonged drug
activity
- Creates a more polar compound
facilitating excretion
CELLULAR MECHANISM
1. Oxidation
- Addition of oxygen or removal of
hydrogen
- Predominant method of drug
biotransformation in the body
- Drug microsomal metabolizing system
(DMMS) enzymes are located in the
smooth ER of specific cells
2. Reduction
- Remove oxygen or add hydrogen
3. Hydrolysis
- Broken down into separate parts
4. Conjugation
- Metabolite is coupled or bound to and
endogenous substance like acetyl CoA,
glucoronic acid or an amino acid
Phase I: 1 to 3
Phase II: 4
DRUG EXCRETION PARAMETERS USED
ROUTES 1. Clearance (CL)
A. Kidney - Predicts the rate of elimination in
- Primary site for drug excretion relation to drug concentration
- Polar compounds will be excreted in - Ability of all organs and tissues or of a
significant amounts because localized single organ or tissue to eliminate the
form has greater tendency to remain drug
in the nephron and not be reabsorbed 2 Primary factors
into the body a. Blood floow
RENAL TRANSPORT b. Extraction ratio – fraction of the
Passive reabsorption drug removed from the plasma as
Active Transport: proximal convoluted it passes through the organ
tubule
- Organic acids DOSING SCHEDULE AND PLASMA
- Organic bases CONCENTRATION
Transport for EDTA Therapeutic Range
B. Lungs
- Volatile drugs administered by VARIATION IN DRUG RESPONSE AND
inhalation METABOLISM
C. GIT 1. Genetic Factors
- Liver into the body and reach - Absence of drug-metabolizing
duodenum via bile duct to the feces enzymes
D. Sweat 2. Diseases
E. Saliva - Structural or functional damage may
F. Breast Milk affect drug metabolism/excretion
3. Drug Interaction
ORGANS RESPONSIBLE FOR METABOLISM - Synergetic vs additive effect
1. Liver - Inhibitory vs competitive
- Primary location for drug metabolism; 4. Age
DMMS enzymes are abundant - Extremes of ages are more sensitive to
2. Lungs drugs
3. Kidneys 5. Diet
4. GIT - Caloric input may affect
5. Skin pharmacokinetics
6. Sex
ENZYME INDUCTION 7. Others
- Prolonged use of drugs “induces” the Environmental/Occupation – smoking or
body to be able to enzymatically alcohol
destroy the drug more rapidly Exercise
- Cause drugs to be metabolized more Obesity
rapidly than expected thus decreasing
their therapeutic effect RECEPTORS
- Tolerance is the need for increased - Components of cell to which drug
dosage of the drug to produce the binds
same effect - Component of a cell or organism that
interacts with a drug and initiates the
DRUG ELIMINATION RATES: chain of events leading to the drugs
- Rates at which the drug is eliminated observed effects
is significant in determining the - Largely determine the quantitative
amount and frequency of the dosage relations between dose or
of the drug
 concentration of drug and
pharmacologic effects
- Responsible for selectivity of drug
action
- Mediate the actions of both
pharmacologic agonists and
antagonists
- Most are proteins
Receptor concept has important practical
consequences for the development of drugs and
for arriving at therapeutic decisions in clinical
practice due to the ff:
1. Receptors largely determine the
quantitative relations between dose or
concentration of drug and pharmacologic
effects
2. Receptors are responsible for selectivity
of drug action
3. Receptors mediate the actions of both
pharmacologic agonists (activate a
receptor to signal as a direct results of
binding) and antagonists (bind to
receptors but do not activate generation
of a signal and interfere with the ability of
an agonist to activate the receptor)
Can Affect Cell Function by:
1. Acting as ion channel
- Increase membrane permeability
- Ex: Acetylcholine-Na influx
2. Act as enzymes
A. Binding domain
- After biochemical function
B. Catalytic domain
- Receptor enzyme systems are often
referred to as “protein tyrosine
kinases”
- Ex: insulin
3. Linking to regulatory proteins
SECONDARY MESSENGER:
G Proteins
Stimulatory – responsive to different drugs
Inhibitory
Adenyl Cyclasae (cAMP), cGMP,
diacylglycerol, Ca ion
Alteration of G protein synthesis/function
Alcoholism, Diabetes, Heart Failure
Tumors
INTRACELLULAR RECEPTORS
- Initiate changes in mRNA
- Cytoplasm
- Nucleus
- E.g. steroid and steroid-like
compounds usually interact with a
receptor located in the cytoplasm
- Thyroxine with receptor located in the
chromatin in the cell’s nucleus
DRUG-RECEPTOR INTERACTION
AFFINITY
- Used to describe the amount of
attraction between a drug and a
receptor
CLASSIFICATION OF DRUGS
A. AGONIST
- Affinity: refers to the attraction or
desire for the drug to bind to a given
receptor
- Efficacy: Indicates that the drug will
activate the receptor and
subsequently lead to a change in the
function of the cell
B. ANTAGONIST
- Often referred to as blockers
- Affinity
a. Competitive: vie for the same
receptor as the agonist; form weak
bonds with the receptor and can
be displaced from the receptor by
a sufficient concentration for
agonist molecules
b. Noncompetitive: have either an
extremely high affinity for the
receptor or form irreversible
covalent bonds
C. PARTIAL AGONISTS
- Do not evoke maximal response
- Having an efficacy that lies between
that of a full agonist and a full
noncompetitive agonist
- Often have a high affinity for the
receptor
- Decreased efficacy may be caused by
the fact that the partial agonist does
not completely activate the receptor
after it binds and that binding results
in a lower level of any postreceptor
events (e.g. less activation of G
 proteins, smaller changes in enzyme
function)

RECEPTOR SUPERSENTIVITY
- A prolonged decreased in the
stimulation of the postsynaptic
receptors result in a functional
increase in receptor sensitivity
- E.g. denervation supersensitivity
- Lack of presynaptic neurotransmitter
results in a compensatory increase in
postsynaptic receptor numbers

NONRECEPTOR DRUG MECHANISM

- Affect membrane
fluidity/organization
- Act as anti-metabolites
- E.g. Cancer chemotherapeutic agents
- Act as chelating agent or by directly
altering enzyme function

RECEPTOR REGULATION
1. Endogenous Factors
- Neurotransmitters, hormones
2. Exogenous Factors
- Drugs

Overstimulation of postsynaptic receptors by

endogenous and exogenous substances may lead
to a functional decrease in the receptor
population

1. Desensitization
- Brief/transient decrease in
responsiveness due to addition of
phosphate residues (phosphorylation)
2. Down-regulation
- Slower process in which the actual
number of available receptors is
diminished which results in a
decrease in responsiveness that
remains long after the agonist is
removed