GENERAL PRINCIPLES OF PHARMACOLOGY Drug Receptor Bonds

Chemical forces or bonds thru which

Pharmacology
the drug interacts with the receptors
- Body of knowledge with the action of
Weaker bonds are more selective bonds
chemicals on biologic systems,
Covalent Bonds
especially by binding to regulatory
Strongest
molecules (receptors) and activating or
Irreversible
inhibiting normal body processes.
Electrostatic Bonds
Medical Pharmacology More common
- Area of pharmacology concerned with Weaker
the use of chemicals in the prevention, Hydrophobic Bonds
diagnosis, and treatment of the disease, Weakest
esp in humans Highly lipid soluble drugs

Toxicology The movement of drugs in the body

- Are of pharmacology concerned with To reach the receptors and bring about
the undesirable effects of chemicals on biologic effect
biologic systems A drug molecule (e.g. sedative) must
travel from the site of administration
Molecular Biology (e.g. GIT)to the site of action (e.g. brain)
Drug any substance that brings about
a change in biologic function thru A. Permeation
chemical actions 1. Aqueous Diffusion
Receptor specific molecule in the Movement of molecules thru the
biologic system that plays a regulatory watery extracellular and
role intracellular spaces
Membranes of capillaries with
The Nature Of Drugs small water-filled pores
Inorganic ions, non-peptide organic Passive process
molecule, small peptides and proteins, Governed by Ficks Law
nucleic acids, lipids, and carbohydrates 2. Lipid Diffusion
Found in plants or animals, many are Movement of molecules thru
partially or completely synthetic membranes and other lipid
structures
Physical Nature Of Drugs
Most important factor for drug
Solid
permeation
Liquid
- Large lipid barriers that
Gas
separate the compartments of
**Drugs are given at a site distant from the
the body
intended site of action.
Passive process
Drug Size And Molecular Weight (Mw) Governed by Ficks Law
Vary in size 3. Transport by Special Carriers
MW 7 (Lithium) Drugs transported across barriers
MW 50,000 (Thrombolytic agents)_ by mechanisms that carry similar
Majority have MW between 100 and endogenous substances
1000 - Amino acid carriers, weak acid
100 MW carriers
For selective binding Capacity limited
1000 MW Not governed by Ficks Law
For traversing to different barriers of Active Transport
the body
- Needs energy
>1000 MW
- Against a concentration
Cannot move w/in the body
gradient
Given directly at the site of action

PHARMACOLOGY LEC (CHAPTER 1) 1 | AEOC

 Facilitated diffusion
- No energy required
- downhill
4. Endocytosis
Binding to specialized
components (receptors)on cell
membranes
Internalization by enfolding of the
area membrane and contents of
the vesicle are subsequently
released into the cytoplasm
Permits very large or very lipid-
insoluble chemicals to enter the
cell
E.g. B12 with intrinsic factor and
iron with transferrin
5. Exocytosis
Reveres process
Encapsulated material from the
cell
B. Ficks Law of Diffusion
Predicts the movement of molecules
across a barrier
Drug absorption is faster in organs
with larger surface areas (e.g. small
intestine) than from organs with
smaller absorbing areas (e.g.
stomach)
( )
C1 higher conc. C2 lower conc.
Permeability coefficient measure of
the mobility of the drug in
medium of the diffusion path.
Thickness length of the diffusion path
C. Water and Lipid Solubility of Drugs
1. AQUEOUS DIFFUSION
Aqueous solubility of a drug is a
function of the electrostatic
charge (degree of ionization,
polarity) of the molecule
Water molecules are attracted to
charged drug molecules forming
an aqueous shell around them
Lipid solubility of a molecule is
inversely proportional to its charge
PHARMACOLOGY LEC (CHAPTER 1)
2. LIPID DIFFUSION
Many drugs are weak bases or
weak acids
pH of the medium determines the
fraction of molecules charged
(ionized) versus uncharged (non-
ionized)
fraction of molecules in the
ionized state can be predicted by
means of the H-H equation
THE HENDERSON-HASSELBACH EQUATION
( )
( )
Protonated means associated with a protein (a
hydrogen ion)
3. IONIZATION OF WEAK ACIDS AND
WEAK BASES
WEAK BASES
- Neutral molecule that can
form a cation (+ charged_
by combining with a proton
(hydrogen ion)
RNH3+ RNH2 + H+
Protonated weak unprotonated weak proton
base (charged, base (uncharged,
more water-soluble) more lipid-soluble)
RCOOH RCOO- + H+
Protonated weak unprotonated weak proton
acid (uncharged, acid (uncharged,
more lipid-soluble) more lipid-soluble)
- Ionized, more polar, molar
water-soluble
WEAK ACID
- Neutral molecule that can
reversibly dissociate into an
anion (- charged) and a
proton ( Hydrogen ion)
- Not ionized, less polar, less
water soluble when they
are protonated
The Henderson-Hasselbach Equation
Clinically important when it is necessary
to estimate or alter the partition of drugs
between compartments of different pH
2 | AEOC
 When a patient takes an overdose of a
weak acid drug, excretion maybe
accelerated by alkalinizing the urine.
Weak acids dissociate to its charged,
polar form in alkaline urine and cannot
readily diffuse back from the renal
tubule back to the blood
Large number of drugs are weak bases
with amine containing molecules
Nitrogen of a neutral amine has 3 atoms
associated with it plus a pair of
unshared electrons
PRIMARY SECONDARY TERTIARY QUATERNARY
H R R R
R N R N R N R N R
H H R R
ABSORPTION OF DRUGS
A. ROUTES OF ADMINISTRATION
Drugs usually enter the body remote
from the target tissue or organ and
require transport by the circulation to
the intended site of action
BIOAVAILABILITY is equal to the
amount absorbed into the systemic
circulation over the amount of drug
administered
1. ORAL (swallowed)
Maximum convenience
Absorption maybe slower, and
less complete
Same drugs have low
bioavailability when given orally
Subject to first pass effect
(significant amount of the agent
is metabolized in the gut wall,
portal circulation, and liver
before it reaches the systemic
circulation)
2. INTRAVENOUS (IV)/ PARENTERAL
Instantaneous and complete
absorption
Bioavailability by definition is
100%
Potentially more dangerous, high
blood levels reached if
administration is too rapid
PHARMACOLOGY LEC (CHAPTER 1)
3. INTRAMUSCULAR (IM)
Absorption is often faster and
more complete (higher
bioavailability) than oral
Large volumes (>5 mL into each
buttock) if the drug is not irritating
First pass effect is avoided
Heparin cannot be given by this
route, causes bleeding in the
muscle
4. SUBCUTANEOUS
Slower absorption than IM route
First pass effect is avoided
Heparin can be given by this
route, does not cause
hematoma
5. BUCCAL AND SUBLINGUAL
Buccal route (in the pouch
between gums and cheeks)
Permits absorption direct into the
systemic circulation, bypassing
hepatic portal circuit and first-
pass metabolism
Slow or fast depending on
formulation of the product
Sublingual route (under the
tongue) offers the same features
6. RECTAL (suppository)
Partial avoidance of first-pass
effect (not completely as the
sublingual route)
Suppositories tend to migrate
upward in the rectum where
absorption is partially into the
portal circulation
Larger amounts of unpleasant
drugs are better administered
rectally
May cause significant irritation
7. INHALATION
For respiratory disease
Delivery closest to the target
tissue
Results into rapid absorption
because of the rapid and thin
alveolar surface area
Drugs that are gases at room
temperature (eg. nitrous oxide),
or easily volatilized (anesthetics)
3 | AEOC
 8. TOPICAL
Application to the skin or mucous
membrane of the eye, nose,
throat, airway, or vagina for local
effect
Rate of absorption is slower
compared to other routes
9. TRANSDERMAL
Application to the skin for
systemic effect
Rate of absorption occurs very
slowly
First-pass effect is avoided
B. BLOOD FLOW
Influences absorption from IM,
subcutaneous, and in shock
High blood flow maintains a high
drug depot-to-blood
concentration gradient
- Maximizes absorption
C. CONCENTRATION
Concentration gradient
Major determinant of the rate of
absorption (Ficks Law)
DISTRIBUITION OF DRUGS
A. DETRMINANTS OF DISTRIBUTION
1. SIZE OF THE ORGAN
Size of the organ determines
the concentration gradient
between blood and the
organ
Eg. skeletal muscle and brain
2. BLOOD FLOW
Important determinant of the
rate of uptake
Well-perfused organs
- Brain
- Heart, kidneys
- Splanchnic organs
3. SOLUBILITY
If the drug is very soluble in
cells, the concentration in the
perivascular space will be
lowered and diffusion from
the vessel into the
extravascular tissue will be
facilitated
4. BINDING
PHARMACOLOGY LEC (CHAPTER 1)
Binding of drugs to
macromolecules in the blood
or tissue compartment will
tend to increase the drugs
concentration in that
compartment
B. APPARENT VOLUME OF DISTRIBUTION
1. Vd
Amount of drug in the body
to concentration in the
plasma
METABOLISM OF DRUGS
A. AS MECHANISM OF TERMINATION OF
DRUG ACTION
Action of many drugs is
terminated before they are
excreted
Metabolized to biologically
inactive derivatives
Conversion to a metabolite is
a form of elimination
B. AS MECHANISM OF DRUG ACTIVATION
PRODRUGS
Inactive as administered and
must be metabolized in the body
to become active
- Eg. levodopa, minoxidil
Many drugs are active as
administered and have active
metabolites as well
- Some benzodiazepines
C. DRUG ELIMINATION WITHOUT
METABOLISM
Drugs not modified by the body
Continue to act until they are
excreted
Eg. lithium
ELIMINATION OF DRUGS
Determinants of the duration of action for most
drugs
Dosage
Rate of elimination following the last
dose
- Disappearance of the active
molecules from the bloodstream
Drug elimination is not the same as drug
excretion
4 | AEOC
 A drug may be eliminated by B. ZERO ORDER ELIMINATION
metabolism long before the modified Rate of elimination is constant
molecules are excreted from the body regardless of concentration
For most drugs, excretion is by way of Occurs with drugs that saturate
the kidneys (except anesthetic gases their elimination of mechanism at
lungs) concentrations of clinical interest
For drugs with active metabolites (eg. Concentration of such drugs in
diazepam), elimination of the parent plasma decrease in linear fashion
molecule by metabolism is not over time
synonymous with termination of action With higher doses, there will be
For drugs that are not metabolized, bigger chances of toxic effect
excretion is the mode of elimination because the patient may not be
A small number of drugs combine able to eliminate it
irreversibly with their receptors, Eg. alcohol, phenytoin, aspirin
disappearance from the bloodstream is
not equivalent to cessation of drug ZERO ORDER KINETICS
action 2.5 units/h
Very prolonged action
Eg. phenoxybenzamine, irreversible Plasma
inhibitor of alpha receptors is eliminated Conc. (Cp) 2.5 units/h
from the bloodstream in 1 hour or less
after administration, drugs action lasts
for 48 hours 2.5 units/h
A. FIRST ORDER ELIMINATION
Rate of elimination is
Time (h)
proportionate to the
concentration (ie., the higher the
conc, the greater the amount
eliminated per unit time)
Drugs conc in plasma decreases
exponentially with time
Half-life elimination is constant
regardless of amount of drug in
the body
Concentration of such drug in
the blood will decrease by 50%
for every half-life
Most common process
Followed by most drugs
FIRST ORDERKINETICS

5 units/h

Plasma
Conc. (Cp) 2.5 units/h

1.25 units/h

Time (h)

PHARMACOLOGY LEC (CHAPTER 1) 5 | AEOC