Basic definitions: 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”
Basic detentions: Drug
• Drug is a chemical substance of known structure
that brings about a change in biologic function
through its chemical actions
• To count as a drug, the substance must be
administered as such, rather than released by
physiological mechanisms
The nature of drugs
• In order for a drug to interact with it’s target, a
drug must have the appropriate:
1)
2)
3)
4)
Size
Electrical Charge
Shape
Atomic composition
Drug-Body Interactions
• The time course of therapeutic drug action in the body
can be understood in terms of pharmacokinetics and
pharmacodynamics
• Pharmacokinetics: the actions of the body on the drug
and includes absorption, distribution, and elimination
• Pharmacodynamics: the actions of the drug on the
body
Pharmacokinetic principles: ADME
1.Absorption: Movement of a drug from its site of
administration into the central compartment (blood
stream)
2.Distribution: Drug movement to various sites/ site of
action
3.Biotransformation/metabolism: Alteration of chemical
structure of drug
4.Excretion: Ability of living system to remove a drug
and its biotransformation products (metabolites) from
the internal environment
METABOLISM
EXCRETION
OTHER TISSUES
DOSE
BLOOD
ABSORPTION
ACTIVE
SITE
RESPONSE
DISTRIBUTION
PHARMACOKINETICS
PHARMACODYNAMICS
Prescribed Dose
Absorption
Most Tissues:
Nonspecific binding
Plasma
Protein Bound
Free Drug
Target Tissue:
Receptor binding
Elimination
Metabolism
Distribution
Renal
Excretion
Effect
Pharmacokinetic principles
a. Permeation
• For a drug to produce effect site of action, it should be
able to cross/ translocate/ penetrate through the various
barriers/ membranes between the site of administration
to the site of action
• There are four main ways by which drugs/ molecules
cross through the various barriers
– Aqueous diffusion
– Lipid diffusion
– Special carriers
– Endocytosis and exocytosis
Routes by which solutes can traverse cell membranes. (Molecules
can also cross cellular barriers by pinocytosis.)
Fick's law of Diffusion
• Describes the passive flux of molecules down a
concentration gradient:
Rate=
(C1 – C2) x
Area x Permeability coefficient
Thickness
Where C1 is the higher conc.; C2 is the lower conc. area is the area across which the diffusion is
occurring. In the case of lipid diffusion, the lipid: aqueous partition coefficient is a major determinant
of mobility of the drug
Ionization of weak acids and weak bases; the HendersonHasselbalch equation
• Most drugs are either week acids (HA) or weak bases (BH+)
• Ionization of drug may decrease their ability to permeate
membranes since the drug becomes more water soluble
when ionized
• Non-ionized molecules are usually lipid soluble and can
diffuse across membrane
• Drug mobility is determined by lipid to water/ aqueous
partition coefficient
• The ratio between the two forms is determined by the pH
and the strength of the weak acid or base, which is
represented by the pKa value
C. Ionization of weak acids and weak bases; the
Henderson-Hasselbalch equation
• Weak acid (HA): a neutral
molecule that can reversibly
dissociate into an anion (A-) and
a proton (H+)
• Weak acids need to become
protonated (uncharged) to be
more lipid soluble
C. Ionization of weak acids and weak bases; the
Henderson-Hasselbalch equation
• Weak base: a neutral molecule that
can form a cation (+) by combining
with a proton (H+)
• Weak bases need to become
unprotonated (uncharged) to be
more lipid soluble
Henderson-Hasselbalch Equation
• Equation is clinically important when it is necessary to
accelerate the excretion of drugs by the kidney – in the
case of an overdose by changing the pH of the urine
(increase ionized state to “trap” drug in urine)
• Excretion of weak acids may be accelerated by
alkalinizing the urine – giving bicarbonate I.V.
• Excretion of a weak base may be accelerated by
acidifying the urine - giving ammonium chloride
I.V.
Pharmacokinetics
Pharmacokinetics
• Pharmacokinetic processes include: absorption, distribution,
metabolism & excretion
• Pharmacokinetic parameters include:
o Volume of Distribution (Vd)
o Protein binding (PB)
o Clearance (CL)
o Half-Life (t1/2)
o Bioavailability (F)
What Happens After Drug Administration?
dose of drug
administered
A
drug in systemic
circulation
D
drug at the site of
action
D
drug in non-target
tissues
PK
E
drug metabolized
or excreted
pharmacologic effect
toxicity
clinical response
efficacy
PD
I. Absorption
• Definition: the transfer of a drug from the
site of administration to the bloodstream.
• The rate and efficacy of absorption depend
on the route of drug administration
• Which is determined primarily by: drug
properties (water or lipid solubility,
ionization, etc.) & therapeutic objectives
Oral Administration
Most drugs are taken by mouth and swallowed
*Advantages
• Safe, most convenient,
and most economical
route of administration
• Toxicities or overdose
may be overcome with
antidotes such as
activated charcoal
• *Disadvantages
• Limited absorption of some drugs
because of their physical characteristics
• Emesis as a result of irritation to the GI
mucosa
• Destruction of some drugs by digestive
enzymes or low gastric pH (penicillins)
• Irregularity or inconsistence of
absorption in the presence of food or
other drugs
Oral Administration
Oral
Vascular
Compartment
Stomach
Liver
Duodenum
Portal
circulation
Interstitial
Water
Cellular
Compartment
Oral administration
• Mechanism of drug absorption:
– Mostly through passive transfer at a rate
determined by the ionisation and lipid solubility of
the drug molecules
– Carrier mediated transport (e.g. Levodopa)
• Site of absorption: small intestine (duodenum) is
the major site for drug absorption because of its large
absorptive surface (approximately 200 m2)
Small intestine (duodenum) is the major site for drug absorption
because of its large absorptive surface (approximately 200 m2)
Stomach
pH =1-2
Intestine
pH = 3-6
Factors affecting GI absorption
1. Gastric emptying time
2. Intestinal motility
3. Food
3.
4.
5.
6.
7.
8.
9.
Drugs
Perfusion of the Gastrointestinal Tract
Particle size and formulation
Solubility of the drug
Reverse transporters (p-glycoprotein)
Chemical instability
First pass metabolism
Elimination
• Is the irreversible loss of drug from the body
• It occurs by two processes: Excretion & Metabolism
• Kidney and liver are the most common organs of drug
elimination
• The kidney is the most important organ for excreting
drugs and their metabolites
Metabolism
• Involves enzymatic conversion of one chemical entity
to another within the body
• The metabolism of drugs into more polar metabolites
is essential for their elimination from the body, as well
as for termination of their biological and
pharmacological activity
• The liver is the major site for drug metabolism
• Specific drugs may undergo biotransformation in
other tissues, such as the kidney and the intestine
Metabolism
• The enzyme systems for drug metabolic
biotransformation reactions can be grouped into
two categories:
1) Phase I oxidative or reductive enzymes
2) Phase II conjugative enzymes
Drug metabolism: Liver
Drug molecule
I
More hydrophilic
metabolite
Conjugate
II
Bile
Kidney
Urine
Intestines
Feces
De-conjugation
and reuptake
(entero-hepatic
cycling)
Phase I reactions
• Phase 1 reactions are catabolic (e.g. oxidation, reduction,
hydrolysis), they often introduce a reactive group, such as (-OH, NH2, -SH), into the molecule
• Phase I metabolism may increase, decrease, activate (prodrug,
e.g. enalapril) or leave unaltered the drug’s pharmacologic
activity
• Phase I reactions are catalyzed by the cytochrome P450 (CYP450)
system
• Six CYP450 isoforms are responsible for the vast majority of
CYP450-catalyzed reactions: CYP3A4, CYP2D6, CYP2C9/10,
CYP2C19, CYP2E1, and CYP1A2
Phase II reactions
• Are
“conjugation reactions” That include glucuronidation,
sulfation, methylation, acetylation, glutathione and amino acid
conjugation.
• The highly polar conjugates generally are inactive (morphine 6glucuronide is an exception) and are excreted rapidly in the
urine and faeces
Volume of distribution (Vd)
• Definition: hypothetical volume of fluid into which a drug is
dispersed
• It relates the amount of drug in the body to the
concentration of drug (C) in blood or plasma:
Vd =
Amount of drug in body
C
• It doesn’t not normally reflect physiological volume
• It is the volume apparently necessary to contain the
amount of drug homogeneously at the concentration found
in the blood, plasma, or water (apparent Vd)
Distribution: body fluid compartments
Plasma
Water
5%
Interstitial
Water
16%
Intracellular
Water
35%
Fat
20%
Transcellular
Water
2%
Volume of distribution (Vd)
Drugs confined to the plasma compartment (plasma
volume 0.05L/kg BWT) (e.g. heparin and warfarin) very
large MWHT, low lipid solubility, or high protinbinding
Drugs distributed in the extracellular compartment
(intracellular volume
0.2L/kg) (e.g. aminoglycoside
antibiotics): low molecular weight and hydrophilic
Drug distributed throughout the body water (total body
water 0.55L/Kg) (e.g. Ethanol): lipid-soluble drugs that
readily cross membrane
Drugs that are extremely lipid soluble (e.g. thiopental)
may have unusually high volume of distribution
Protein binding
• Many drugs circulate in the bloodstream bound to plasma
proteins
• Albumin is a major carrier for acidic drugs and α1-acid
glycoprotein (AAG) binds basic drugs
• The binding is usually reversible
• Binding of a drug to plasma proteins limits its
concentration in tissues including organ of elemination
and at its site of action
• It is affected by disease-related factors (hypoalbuminemia)
and drug-drug interactions
Clearance (CL)
• The main PK parameter describing elimination & is
the most important concept to consider when
designing a rational regimen for long-term drug
administration
• Definition: the volume of plasma/fluid that is cleared
of drug that is removed from the body in unit time
Conc in
Eliminating
Organ
Kidney, liver, etc.
Conc
eliminated
Conc out
Clearance (CL)
• Drug clearance depends on:
1) Extraction ratio: a measure of the efficiency
with which an organ of elimination can remove
the drug from the blood
2) Blood flow rate: the rate of drug delivery to the
eliminating organ
CL = Q x ER
Half-Life (t1/2)
• Definition: it is the time required for the plasma
concentration or the amount of drug in the body to
change by one-half (i.e. 50%)
• The half-life is a derived parameter that changes as a
function of both clearance and volume of distribution.
A useful approximate relationship between the
clinically relevant half-life, clearance, and volume of
distribution is given by:
t1/2 =
0.693 × Vd
CL
Drug Concentration
C1
1/2C1
t1
t2
t1/2
Time
Knowledge about half-life is useful in determining the time to
reach/attain steady state (ss) or to decay from steady state conditions
Accumulation to Steady State 100 mg given every half-life
175
187.5
194
…
200
150
100
87.5
94
97
…
75
50
4-5 half lives to reach steady state
100
Rational dosage design
• Is based on the assumption that there is a target
concentration that will produce the desired
therapeutic effect
• The intensity of a drug's effect is related to its
concentration
above
a
minimum
effective
concentration, whereas the duration of this effect
reflects the length of time the drug level is above this
value
Loading dose
• Is one or a series of doses that may be given at the
onset of therapy with the aim of achieving the target
concentration rapidly
• The appropriate magnitude for the loading dose is:
Loading dose = TC × Vd
Maintenance dose
• Aseries of repetitive doses to achieve and
maintain a steady-state concentration of drug
• Just enough drug is given in each dose to replace
the drug eliminated since the preceding dose:
Rate in = Rate out
Maintenance dose
• Clearance is the most important pharmacokinetic
term to be considered in defining a rational steady
state drug dosage regimen:
Maintenance dose = CL × TC
CL= clearance; TC= target concentration