The dose of propranolol administered intravenously is less than that administered orally because of first pass effect through the liver.
When a drug is administered orally, it is absorbed through the gastrointestinal tract and enters the portal circulation, which carries blood directly from the intestines to the liver. This exposes the drug to high concentrations of hepatic drug metabolizing enzymes before it reaches systemic circulation. Many drugs, including propranolol, are extensively metabolized in the liver during first pass. This reduces the amount of unchanged/active drug that reaches the systemic circulation compared to intravenous administration, which bypasses first pass metabolism. Therefore, a higher oral dose is needed to achieve the same systemic drug concentration as a lower intravenous dose.
2. BASIC TERMINOLOGIES
Drug any substance that interacts with a
molecule or protein that plays a
regulatory role in living systems.
3. Introduction to biopharmaceutics:
Biopharmaceutics: the study of how the
physicochemical properties of drugs, dosage
forms and routes of administration affect the rate
and extent of the drug absorption.
Thus, biopharmaceutics involves factors that
influence the:
1) protection and stability of the drug within the
product;
2) the rate of drug release from the product;
3) the rate of dissolution of the drug at the
absorption site; and
4) the availability of the drug at its site of action .
4. Generally, the GOAL of
biopharmaceutical studies is to
develop a dosage form that will
provide consistent bioavailability at a
desirable rate.
5. Pharmacokinetics – “what the body DOES to the
drug”. This phase of drug delivery system involves
ADME
Pharmacodynamics – “what the drug DOES to
the body”; the biochemical & physical effects of
drugs on the body & the mechanism of drug action.
Pharmacotherapeutics – the use of drugs to
prevent and treat diseases.
BASIC TERMINOLOGIES
7. Pharmacokinetics vs
Pharmacodynamics…concept
If Fluoxetine is given with Tramadol, serotonin
syndrome can result. This is a
pharmacodynamic drug interaction.
Fluoxetine and Tramadol both increase
availability of serotonin leading to the
possibility of “serotonin overload” This
happens without a change in the
concentration of either drug.
8.
9. 9
Dynamic Relationship
Drug release
and
dissolution
Drug in Systemic
circulation
Pharmacologic or
clinical response
Excretion and
metabolism
Drug in tissuesAbsorption
Elimination
Relationship between the drug, the drug
product and the pharmacologic effect
BIOPHARMACEUTICS
PK PD
10.
11. Applications of Pharmacokinetic studies:
1. Pharmacological testing – assess
the relationship bet the drug C and
pharmacological activities. This is
important to determine how much
and how often the drug should be
given.
2. Toxicological testing – assess tissue
accumulation of drugs and how it is
related to drug toxicity.
12. Applications of Pharmacokinetic studies:
3. Evaluation of Organ Function –
evaluate the function of eliminating
organs.
4. Dosage Regimen Design – design
the dosing regimen (dose and
dosing interval of a specific drug)
that can achieve the maximum
therapeutic effect w/ minimal
toxicity.
14. Bioavailability: The rate and extent of drug absorption.
Bioavailable dose: The fraction of an administered
dose of a particular drug that reaches the systemic
circulation intact.
Plasma level-time curve:
15. The plasma level-time curve is generated by
measuring the drug concentration in plasma
samples taken at various time intervals after a drug
product is administered.
The concentration of drug in each plasma sample is
plotted against the corresponding time at which the
plasma sample was removed.
16.
17. Drug Product Performance Parameters:
1- Minimum effective concentration (MEC): The
minimum concentration of drug needed at the receptors to
produce the desired pharmacologic effect.
2- Minimum toxic concentration (MTC): The drug
concentration needed to just produce a toxic effect.
3- Onset time: The time required for the drug to reach the
MEC.
4- Duration of action: The difference between the onset
time and the time for the drug to decline back to the MEC.
18. 5- The time of peak plasma level: The time of
maximum drug concentration in the plasma and is
proportional to the rate of drug absorption.
6- The peak plasma level: The maximum drug
concentration, usually related to the dose and the
rate constants for absorption and elimination of
the drug.
7- Area under the curve: It is related to the
amount of drug absorbed systemically.
19. • chemical nature of a drug
• Inert excipients
• method of manufacture
• physicochemical properties of drug
such as pKa, particle size, partition
coefficient, polymorphism etc.
Factors influencing the BIOAVAILABILITY
of a Drug
22. Drug Concentration In Tissues
Tissue biopsies used for verification of
malignancy.
Small sample is removed, hence measurement of
drug concentration difficult.
Used to ascertain if the drug reached the tissue &
reached the proper concentration within the
tissues.
23. Drug Concentrations in Urine & Feces
It is an indirect method to ascertain the
bioavailability of a drug.
The rate & extent of drug excreted in urine
reflects the rate & extent of systemic drug
absorption.
Measurement of drug in feces may reflect drug
that has not been absorbed after an oral dose or
may reflect drug that has been expelled by biliary
secretion after systemic absorption.
24. Used for TDM because only free drug diffuse into
the saliva, saliva drug levels tend to approximate
free drug rather than total plasma drug conc.
The ratio of saliva/plasma drug concentration ratio
less than 1 for many drugs.
It is influenced by pKa of a drug & pH of the saliva.
Drug Concentration in Saliva
25. 2 General Classifications of Drugs
BASIC TERMINOLOGIES
1. Endogenous
2. Exogenous
1. Hormones
2. Neurotransmitters
3. Mediators
3 groups of endogenous
chemical messengers/drugs
that target receptors
26. 1. Hormones - produced by endocrine
tissue and carried in the blood to their
receptor targets.
e.g. adrenaline, insulin, ADH-vasopressin and
aldosterone
2. Neurotransmitters - released by neuron
terminals; chemical messengers bind
to receptors on neurons and other cells,
either stimulating or inhibiting activity
in those cells.
e.g. noradrenaline, acetylcholine and serotonin (5-HT)
28. 3. Mediators - locally acting chemical
messengers released by cells and
having an effect on adjacent cells.
e.g.
histamine
leukotrienes
29. PHARMACOKINETIC PRINCIPLES
Routes of administration are determined by:
1. Properties of the drug
2.Therapeutic objectives
2 major routes of administration:
1. Enteral (extravascular) - administering the drug by
mouth; the simplest and most common
2.Parenteral (intravascular)- introduces drugs directly
across the body’s barrier defenses into the systemic
circulation or other vascular tissue.
3.Others
31. Injection is the most common parenteral route.
Enteral has advantages:
~ Can be self administered
~ Limits systemic infections that could
complicate treatment
~ Toxicities or overdose may be overcome
with antidotes.
The Universal Antidote is a
mixture that contains
activated charcoal,
magnesium oxide, and
tannic acid.
32. Enteral can be further classified into:
A. Oral
B. Sublingual
C. Buccal
D. Sublabial
E. Perlingual
33. Parenteral has Advantages
Fast: 15–30sec for IV, 3–5 mins for IM and SC
100% bioavailability
suitable for drugs not absorbed by the digestive
system or those that are too irritant
One injection can be formulated to last days or
even months, e.g. Depo-Provera
IV can deliver continuous medication, e.g.,
morphine for patients in continuous pain, or
saline drip for people needing fluids
35. Topical local effect, substance is applied directly
where its action is desired; applied to a localized
area of the body or to the surface of a body part or
through mucous membranes in the body.
epicutaneous
enemas
eye
drops
ear drops
49. Membranes
Types of Membranes:
Cell Membranes: This barrier is permeable to many
drug molecules but not to others, depending on their
lipid solubility. Small pores, 8 angstroms, permit small
molecules such as alcohol and water to pass through.
Walls of Capillaries: Pores between the cells are
larger than most drug molecules, allowing them to pass
freely, without lipid solubility being a factor.
Blood/Brain Barrier: This barrier provides a
protective environment for the brain. Speed of transport
across this barrier is limited by the lipid solubility of the
psychoactive molecule.
Placental Barrier: This barrier separates two distinct
human beings but is very permeable to lipid soluble
drugs.
54. LADMER Processes
can be divided into two
classes:
a. drug input
b. drug output
INPUT PROCESSES are:
L = Liberation, the release of
the drug from it's dosage form.
A = Absorption, the movement
of drug from the site of
administration to the blood
circulation.
55. FACTORS AFFECTING LIBERATION
1. Surface area
“the larger the surface area exposed to
the solvent, the faster the
dissolution rate.”
2. Solubility
For weakly acidic drugs, solubility
increases w/ an increasing pH of the
solvent.
For basic drugs, solubility increases
with decreasing pH.
56. Despite the effect of pH on the intrinsic solubility
of the drug compound, there are cases of
compounds with poor aqueous solubility. In such
cases, the solubility of the drug in water is
sometimes enhanced by the formation of salts.
“salts of the weak acids and salts of weak bases
generally have much better aqueous solubility
than the corresponding free acid or free base.”
57. FACTORS AFFECTING LIBERATION
3. Crystal or Amorphous Form
“the amorphous form is more soluble
than the crystalline form.”
4. Agitation
5. State of hydration
“Anhydrous form of the drug is more
readily soluble than the hydrated one.”
6. Drug Design
58.
59.
60. INPUT PROCESSES
Bioavailability
describes the rate and
extent of drug input. The
fraction of administered
drug that reaches
systemic circulation.
IV route drugs 100%
bioavailability.
61. ABSOLUTE BIOAVAILABILITY
Is the measurement of a test formulation dose
against an IV reference dose the bioavailability
of which is 100% by definition.
Absolute
Bioavailability
%
=
AUC test / Dose test
X 100AUC IV / Dose IV
62. RELATIVE BIOAVAILABILITY
Is the measurement of a test formulation dose
against a reference formulation. The two
formulations are may be considered
bioequivalent if the range of the ratio of their
AUCS is 0.8 to 1.25.
Relative
Bioavailability
%
=
AUC test / Dose test
X
100
AUC reference / Dose reference
63. FACTORS THAT INFLUENCES BIOAVAILABILITY
(additional):
a.First-pass hepatic metabolism
b.Solubility of the drugs
“for a drug to be readily absorbed, it should be largely
hydrophobic, yet have some solubility in aqueous solutions.”
c. Chemical instability
d. Nature of drug formulation
BIOEQUIVALENCE If 2 related drugs show
comparable bioavailability and similar times to achieve peak
blood concentrations.
THERAPEUTIC EQUIVALENCE 2 similar drugs are
therapeutically equivalent if they have comparable efficacy
and safety.
64. OUTPUT PROCESSES
D = Distribution, process by w/c a drug
reversibly leaves the bloodstream and enters
the interstitium (extracellular fluid) and/or
the cells of the tissues.
65. Drug Distribution
Dependent upon its route of administration and target area, every
drug has to be absorbed, by diffusion, through a variety of bodily
tissue.
Tissue is composed of cells which are encompassed within
membranes, consisting of 3 layers, 2 layers of water-soluble complex
lipid molecules (phospholipid) and a layer of liquid lipid, sandwiched
within these layers. Suspended within the layers are large proteins,
with some, such as receptors, transversing all 3 layers.
The permeability of a cell membrane, for a specific drug, depends on
a ratio of its water to lipid solubility. Within the body, drugs may exist
as a mixture of two interchangeable forms, either water (ionized-
charged) or lipid (non-ionized) soluble. The concentration of two
forms depends on characteristics of the drug molecule (pKa, pH at
which 50% of the drug is ionized) and the pH of fluid in which it is
dissolved.
In water soluble form, drugs cannot pass through lipid membranes,
but to reach their target area, they must permeate a variety of types
of membranes.
66. M = Metabolism, the chemical conversion or
transformation of drugs into compounds which are
easier to eliminate.
E = Excretion, the elimination of unchanged drug
or metabolite from the body via renal, biliary, or
pulmonary processes.
R = Response, the action of the body to the drug
administered
OUTPUT PROCESSES
67. Presystemic metabolism:
Definition:The metabolism of orally administered drugs by
gastrointestinal and hepatic enzymes, resulting in a
significant reduction of the amount of unmetabolized drug
reaching the systemic circulation.
Gut wall metabolism
- This effect is known as first-pass metabolism by the
intestine.
- Cytochrome P450 enzyme, CYP3A, that is present in the
liver and responsible for the hepatic metabolism of many
drugs, is present in the intestinal mucosa and that
intestinal metabolism may be important for substrates of
this enzyme e.g. cyclosporin.
-
68. Presystemic metabolism:
Hepatic metabolism
- After a drug is swallowed, it is absorbed by the digestive
system and enters the hepatic portal system. It is carried
through the portal vein into the liver before it reaches the
rest of the body.
- The liver metabolizes many drugs (e.g. propranolol),
sometimes to such an extent that only a small amount of
active drug emerges from the liver to the rest of the
circulatory system.
- This first pass through the liver thus greatly reduces the
bioavailability of the drug.
71. PORTAL CIRCULATION
When the drug is taken orally, absorption will most
probably happen in the small intestine.
The drug is considered absorbed when it is transported
from the lumen of the small intestine into the blood
stream. Blood drained from the small intestine is first
passed on to the liver through the portal vein before
being released into the systemic circulation.
Drugs that are absorbed through the portal vein may be
subjected to liver activity before being released into the
systemic circulation.
portal circulation refers to the
circulation of the blood from
the small intestine to the liver,
via the portal vein. Blood flow
to the liver is unique in that it
receives oxygenated and de-
oxygenated blood.
72.
73.
74. FIRST PASS EFFECT
First pass effect is the inactivation of drugs by the liver
immediately after absorption through the portal
circulation.
The liver metabolizes many drugs altering the
concentration of the active drug that will eventually be
released into the systemic circulation.
First pass effect may greatly reduce bioavailability of a
drug.
75. The dose of propranolol
administered intravenously is
less than that administered
orally. Why is this so?
76. Examine the schematic
diagram of the different
routes of drug administration
showing potential for first
pass effect and how it can
affect bioavailability.
77.
78. In your lesson plan, discuss the
schematic diagram and answer
the following questions:
1.Give 2 enteral and 2 topical routes of
administration that bypass first pass effect.
2.If you want to insert a box for percutaneous
administration in the above illustration. Where will
you put it?
79. Absorption
Main factors affecting oral absorption:
I Physiological factors.
II Physical-chemical factors.
III Formulation factors.
I Physiological factors affecting oral absorption:
1- Membrane physiology.
2- Passage of drugs across membranes.
3- Gastrointestinal physiology.
I. Characteristics of GIT physiology and drug absorption
II. Gastric emptying time and motility
III. Effect of food on drug absorption
81. 1- Membrane physiology (Cont.):
- The cell membrane is the barrier that separates the inside
of the cell from the outside.
- The cell membrane is made up of phospholipids, proteins,
and other macromolecules.
- The phosopholipids make up a bilayer. It contains
hydrophilic and hydrophobic molecules.
- The proteins in the cell membrane are located within the
phospholipid bilayer.
- So, the biologic membrane is mainly lipid in nature but
contains small aqueous channels or pores.
82. 2-Passage of drugs across membranes:
DRUG TRANSPORT:
1. PASSIVE DIFFUSION
2. CARRIER-MEDIATED
2.1 FACILITATED DIFFUSION
2.2 ACTIVE TRANSPORT
3. PORE, CONVECTIVE, PARACELLULAR
4. VESICULAR TRANSPORT
4.1 ENDOCYTOSIS
4.1.1 PHAGOCYTOSIS
4.1.2 PINOCYTOSIS
4.2 EXOCYTOSIS
5. ION PAIR FORMATION
6. TRANSPORTER PROTEIN EFFLUX
83. 1. Passive diffusion:
- Most drugs cross biologic membranes by passive
diffusion.
- Diffusion occurs when the drug concentration on one side
of the membrane is higher than that on the other side.
- The process is passive because no external energy is
expended.
- The driving force for passive diffusion is the difference in
drug concentrations on either side of the cell membrane.
85. 2. CARRIER- MEDIATED
2.1 Facilitated diffusion:
- Play a very minor role in absorption.
- A drug carrier is required but no energy is necessary. e.g.
vitamin B12 transport.
- Saturable if not enough carrier and structurally selective for
the drug and shows competition kinetics for drugs of
similar structure.
- No transport against a concentration gradient only downhill
but faster.
86. involves specific
carrier proteins that
span a membrane
energy dependent
driven by the
hydrolysis of ATP
capable of moving
drugs against a
concentration
gradient – that is,
from a region of
low concentration
to one of higher
drug
concentration.
2.2 ACTIVE TRANSPORT
87. BOTH DOESN’T REQUIRE ENERGY
The rate of passive transport depends on the permeability of the
cell membrane
SIMILARITIES
DIFFERENCES
> involves a carrier, transmembrane
proteins
> can be saturated
> doesn’t involve a carrier
> not saturable
> shows a low structural
specificity
88. Fick’s First Law of Diffusion
The amount, M, of material flowing through a unit
cross section, X, of a barrier in unit time, t, is known
as the flux, J.
The flux, in turn, is proportional to the concentration
gradient, dC/dt.
“Diffusion will stop when the concentration gradient
no longer exists.”
89. Diagram of Passive Transport with a Concentration Gradient
-The rate of transport of drug across the membrane can be described by Fick's
first law of diffusion:-
Fick's First Law, Rate of Diffusion
90. The negative sign of equation signifies that
diffusion occurs in a direction opposite to
that of increasing concentration.
Diffusion occurs in the direction of decreasing
concentration of diffusant.
91.
92. DRUG TRANSPORT
3- Pore (convective) transport:
- A certain type of protein called transport
protein may form an open channel across
the lipid membrane of the cell.
- Very small molecules, such as urea, water
and sugars are able to rapidly cross the cell
membrane through these pores.
95. Exocytosis: reverse of Endocytosis. Used by
cells to secrete or discharge many substances
by a similar vesicle formation process.
Endocytosis: engulfment of a drug molecule by the cell
membrane and transport into the cell by pinching off the
drug-filled vesicle.
97. 5- Ion pair formation:
-Strong electrolyte drugs are highly ionized or
charged molecules, such as quaternary
nitrogen compounds.
-These drugs penetrate membranes poorly.
When linked up with an oppositely charged
ion, an ion pair is formed in which the overall
charge of the pair is neutral. This neutral
complex diffuses more easily across the
membrane.
- e.g. the formation of an ion pair for
propranolol (basic drug) with oleic acid.
98. 6. Transporter Protein Efflux
Drug transport proteins can be grouped into two
major classes:
a. the solute carriers (SLC) (facilitate the cellular uptake
or influx of substrates, either by facilitated diffusion)
b. ATP-binding cassette (ABC) transporters.
Over 380 unique SLC sequences have been obtained
from the human genome, which can be divided into
48 subfamilies.
ABC transporters are by definition efflux transporters because they use
energy derived from ATP hydrolysis to mediate the primary active export
of drugs from the intracellular to the extracellular milieu, often against a
steep diffusion gradient.
99. Absorption
Main factors affecting oral absorption:
I Physiological factors.
II Physical-chemical factors.
III Formulation factors.
I Physiological factors affecting oral absorption:
1- Membrane physiology.
2- Passage of drugs across membranes.
3- Gastrointestinal physiology.
I. Characteristics of GIT physiology and drug absorption
II. Gastric emptying time and motility
III. Effect of food on drug absorption
100. 3- Gastrointestinal (GI) Physiology:
- The gastrointestinal tract is a muscular tube
approximately 6 m in length with varying diameters.
- It stretches from the mouth to the anus and consists of
four main anatomical areas: the oesophagus, the stomach,
the small intestine and the large intestine or colon.
- The majority of the gastrointestinal epithelium is covered
by a layer of mucous. This is a viscoelastic translucent
aqueous gel that is secreted through out the GIT, acting as
a protective layer and a mechanical barrier.
102. Gastrointestinal (GI) Physiology (Cont.):
I. Characteristics of GI physiology and Drug
Absorption:
Organs pH Membrane Blood
Supply
Surfac
e Area
Transit
Time
By-
pass
liver
Buccal approx
6
thin Good, fast
absorption
with low
dose
small Short
unless
controlled
yes
Oesophagus 5-6 Very thick
no
absorption
- small short,
typically a
few
seconds,
except for
some
coated
tablets
-
103. I. Characteristics of GI physiology and Drug
Absorption (cont.):
Organs pH Membrane Blood
Supply
Surface
Area
Transit
Time
By-pass
liver
Stomach 1.7-3.5 normal good small 30 min
(liquid) -
120 min
(solid food)
no
Duodenum 5 - 7 normal good Very
large
very short, no
104. I. Characteristics of GI physiology and Drug
Absorption (cont.):
Organs pH Membrane Blood
Supply
Surface
Area
Transit
Time
By-pass
liver
Small
Intestine
6 – 7.5 normal good Very
large
About 3
hours
no
Large
intestine
6.8 - 7 - good Not very
large
long, up to
24 hours
Lower
colon,
rectum
yes
105. The environment within the lumen:
Gastrointestinal pH
- As we observed from the previous tables, the pH of fluids varies along
the length of the GIT.
- The gastrointestinal pH may influence the absorption of drugs in a
variety of ways:
A- It may affect the chemical stability of the drug in the lumen e.g.
penicillin G, erythromycin
B- affect the drug dissolution or absorption e.g. weak electrolyte drug
Luminal enzymes
- The primary enzyme found in gastric juice is pepsin. Lipases, amylases
and proteases are secreted from the pancreas into the small intestine.
- Pepsins and proteases are responsible for the digestion of protein and
peptide drugs in the lumen.
I. Characteristics of GI physiology and
Drug Absorption (cont.):
106. - The lipases may affect the release of drugs from fat / oil –
containing dosage forms.
- Bacteria which are localized within the colonic region of
the GIT secrete enzymes which are capable of a range of
reactions.
- e.g. Sulphasalazine which is a prodrug used to target the
colon.
Sulphasalazine active drug
(5-aminosalicylic acid)
treat inflammatory bowel disease
I. Characteristics of GI physiology and Drug
Absorption (cont.):
Bacterial enzymes
107. Disease state and physiological disorders
- Local diseases can cause alterations in gastric pH that can
affect the stability , dissolution and absorption of the
drug.
- Partial or total gastrectomy results in drugs reaching the
duodenum more rapidly than in normal individuals. This
may result in an increased overall rate of absorption of
drugs that are absorbed in the small intestine.
- However, drugs that require a period of time in the
stomach to facilitate their dissolution may show reduced
bioavailability in such patients.
I. Characteristics of GI physiology and Drug
Absorption (cont.):
108. The unstirred water layer
- It is a more or less stagnant layer of water and mucous
adjacent to the intestinal wall.
- This layer can provide a diffusion barrier to drugs.
- Some drugs (antibiotics e.g. tetracycline) are capable of
complexing with mucous, thereby reducing their
availability for absorption.
I. Characteristics of GI physiology and Drug
Absorption (cont.):
109. II Gastric emptying and motility:
- The time a dosage form takes to traverse the stomach is
usually termed: the gastric residence time, gastric
emptying time or gastric emptying rate.
-
- Generally drugs are better absorbed in the small intestine (because of the larger
surface area) than in the stomach, therefore quicker stomach emptying will
increase drug absorption.
- For example, a good correlation has been found between stomach emptying
time and peak plasma concentration for acetaminophen. The quicker the
stomach emptying (shorter stomach emptying time) the higher the plasma
concentration.
- Also slower stomach emptying can cause increased degradation of drugs in the
stomach's lower pH; e.g. L-dopa.
110. II Gastric emptying and motility:
Dependence of peak acetaminophen plasma concentration
as a function of stomach emptying half-life
112. II Gastric emptying and
motility:
Factors Affecting Gastric Emptying
Viscosity Rate of emptying is greater for less viscous
solutions
Emotional states - Stressful emotional states increase
stomach contraction and emptying rate
- Depression reduces stomach contraction
and emptying
Disease states -Rate of emptying is reduced in:
Some diabetic patients, hypothyrodism
-Rate of emptying is increased in:
hyperthyrodism
Exercise Reduce emptying rate
113. III Effect of Food:
- The presence of food in the GIT can influence the rate and
extent of absorption, either directly or indirectly via a range
of mechanisms.
A- Complexation of drugs with components in the diet
e.g.Tetracycline forms non-absorable complexes with calcium
and iron, and thus it is advised that patients do not take
products containing calcium or iron, such as milk, iron
preparations or indigestion remedies, at the same time of
day as the tetracycline.
B- Alteration of pH
Food tends to increase stomach pH by acting as a buffer. This
liable to decrease the rate of dissolution and absorption of
a weakly basic drug and increase that of a weakly acidic
one.
114. III Effect of Food (cont.):
C- Alteration of gastric emptying
Fats and some drugs tend to reduce gastric emptying and
thus delay the onset of action of certain drugs.
D- Stimulation of gastrointestinal secretions
- Gastrointestinal secretions (e.g. pepsin) produced in
response to food may result in the degradation of drugs
that are susceptible to enzymatic metabolism, and hence
a reduction in their bioavailability.
- Fats stimulate the secretion of bile. Bile salts are surface
active agents which increase the dissolution of poorly
soluble drugs (griseofulvin).
Bile salts can form insoluble and non-absorbable
complexes with some drugs, such as neomycin and
kanamycin.
115. III Effect of Food (cont.):
E-Competition between food components and drugs for
specialized absorption mechanisms
There is a possibility of competitive inhibition of drug
absorption in case of drugs that have a chemical structure
similar to nutrients required by the body for which
specialized absorption mechanisms exist.
F- Increased viscosity of gastrointestinal contents
The presence of food in the GIT provides a viscous
environment which may result in:
- Reduction in the rate of drug dissolution
- Reduction in the rate of diffusion of drug in solution from
the lumen to the absorbing membrane lining the GIT.
Hence, there is reduction in drug bioavailability.
116. G- Food-induced changes in presystemic metabolism
- Certain foods may increase the bioavailability of drugs that are
susceptible to presystemic intestinal metabolism by interacting with
the metabolic process.
- E.g. Grapefruit juice is capable of inhibiting the intestinal cytochrome
P450 (CYP3A) and thus taken with drugs that are susceptible to
CYP3A metabolism which result in increase of their bioavailability.
H- Food-induced changes in blood flow
- Food serve to increase the bioavailability of some drugs (e.g.
propranolol) that are susceptible to first-pass metaolism.
- Blood flow to the GIT and liver increases after a meal. The faster the
rate of drug presentation to the liver; the larger the fraction of drug
that escapes first-pass metabolism. This is because the enzyme
systems become saturated.
III Effect of Food (cont.):
117. III Effect of Food (cont.):
Effect of Fasting versus Fed on Propranolol
Concentrations
118. Double peak phenomena:
- Some drugs such as cimetidine and rantidine, after oral
administration produce a blood concentration curve
consisting of two peaks.
- The presence of double peaks has been attributed to
variability in stomach emptying, variable intestinal
motility, presence of food, enterohepatic cycle or failure of
a tablet dosage form.
119. Absorption
Main factors affecting oral absorption:
I Physiological factors.
II Physical-chemical factors.
III Formulation factors.
I Physiological factors affecting oral absorption:
1- Membrane physiology.
2- Passage of drugs across membranes.
3- Gastrointestinal physiology.
I. Characteristics of GIT physiology and drug absorption
II. Gastric emptying time and motility
III. Effect of food on drug absorption
120. II Physical-Chemical Factors Affecting Oral
Absorption:
Physical-chemical factors affecting oral absorption
include:
A- pH-partition theory
B- Lipid solubility of drugs
C- Dissolution and pH
D- Drug stability and hydrolysis in GIT
E- Complexation
F- Adsorption
121. A. pH - Partition Theory:
- According to the pH-partition hypothesis, the
gastrointestinal epithelia acts as a lipid barrier towards
drugs which are absorbed by passive diffusion, and those
that are lipid soluble will pass across the barrier.
- As most drugs are weak electrolytes, the unionized form of
weakly acidic or basic drugs (the lipid-soluble form) will
pass across the gastrointestinal epithelia, whereas the
gastrointestinal epithelia is impermeable to the ionized
(poorly-lipid soluble) form of such drugs.
- Consequently, the absorption of a weak electrolyte will be
determined by the extent to which the drug exists in its
unionized form at the site of absorption.
122. A. pH - Partition Theory (Cont.):
Diagram Showing Transfer Across Membrane
124. A. pH - Partition Theory (Cont.):
- The extent to which a weakly acidic or basic drug ionizes in
solution in the gastrointestinal fluid may be calculated
using Henderson - Hasselbach equation.
** Weak acids (e.g. aspirin):
Dissociation Constant equation - Weak Acids
taking the negative log of both sides
125. A. pH - Partition Theory (Cont.):
Rearranging gives the following equation:
Henderson - Hasselbach Equation - Weak Acids
126. A. pH - Partition Theory (Cont.):
**Weak Bases:
Henderson - Hasselbach Equation - Weak Bases
Limitations of the pH-partition hypothesis:
-Despite their high degree of ionization, weak acids are highly
absorbed from the small intestine and this may be due to:
1- The large surface area that is available for absorption in
the small intestine.
2- A longer small intestine residence time.
127. A. pH - Partition Theory (Cont.):
3- A microclimate pH, that exists on the surface of
intestinal mucosa and is lower than that of the
luminal pH of the small intestine.
128. ABSORPTION OF DRUGS
Physical Factors affecting Absorption.
1. Blood flow to the absorption site
2. Total Surface area available for absorption
3. Contact time at the absorption surface.
Absorption from the intestine is
more favorable.
Parasympathetic input increases gastric
emptying while sympathetic input
prolongs gastric emptying.
129. B. Lipid solubility of drugs:
- Some drugs are poorly absorbed after oral administration
even though they are non-ionized in small intestine. Low
lipid solubility of them may be the reason.
- The best parameter to correlate between water and lipid
solubility is partition coefficient.
Partition coefficient (p) = [ L] conc / [W] conc
where, [ L] conc is the concentration of the drug in lipid
phase.
[W] conc is the concentration of the drug in aqueous phase.
- The higher p value, the more absorption is observed.
130. C. Drug Dissolution:
- Many drugs are given in solid dosage forms and therefore
must dissolve before absorption can take place.
- If dissolution is the slow, it will be the rate determining
step (the step controlling the overall rate of absorption)
then factors affecting dissolution will control the overall
process.
131. C. Drug Dissolution (cont.):
- Drug dissolution is considered to be diffusion controlled
process through a stagnant layer surrounding each solid
particle.
Diagram Representing Diffusion
Through the Stagnant Layer
132. C. Drug Dissolution (cont.):
- The dissolution of drugs can be described by the Noyes-
Whitney equation:
- Where D is the diffusion coefficient, A the surface area, Cs the solubility of the
drug, Cb the concentration of drug in the bulk solution, and h the thickness of the
stagnant layer.
-If Cb is much smaller than Cs then we have so-called "Sink Conditions" and the
equation reduces to
133. C. Drug Dissolution (cont.):
Factors affecting drug dissolution in the GIT:
I Physiological factors affecting the dissolution
rate of drugs:
- The environment of the GIT can affect the parameters of
the Noyes-Whitney equation and hence the dissolution
rate of a drug.
A- Diffusion coefficient, D:
- Presence of food in the GIT increase the viscosity of
the gastrointestinal fluids reducing the rate of
diffusion of the drug molecules away from the diffusion
layer surrounding each undissolved drug particles ( D)↓
decrease in dissolution rate of a drug.
134. C. Drug Dissolution (cont.):
B- Drug surface area, A:
Surfactants in gastric juice and bile salts
increase the wettability of the drug increase the
drug solubility via micellization.
C. The thickness of diffusion layer, h:
An increase in gastric and/or intestinal motility
decrease the thickness of diffusion layer around each drug
particle increase the dissolution rate of a drug.
D. The concentration, C, of drug in solution in
the bulk of the gastrointestinal fluids:
135. C. Drug Dissolution (cont.):
Increasing the rate of removal of dissolved drug by
absorption through the gastrointestinal-blood barrier and
increasing the intake of fluid in the diet will
decrease in C rapid dissolution of the drug.
II Physicochemical factors affecting the dissolution
rate of drugs:
A- Surface area, A:
- The smaller the particle size the greater the
effective surface area of drug particle the higher
the dissolution rate.
136. C. Drug Dissolution (cont.):
- Methods of particle size reduction include: mortar and
pestle, mechanical grinders, mills, solid dispersions in
readily soluble materials (PEG's).
- However very small particles can
clump together. Therefore
a wetting agent such as Tween 80
can have a beneficial effect on
the overall absorption.
137. C. Drug Dissolution (cont.):
B-Diffusion coefficient, D:
The value of D depends on the size of the molecule
and the viscosity of the dissolution medium.
C- Solubility in the diffusion layer, Cs:
- The dissolution rate of a drug is directly
proportional to its intrinsic solubility in the
diffusion layer surrounding each dissolving drug
particle.
138. C. Drug Dissolution (cont.):
D- Salts:
- Salts of weak acids and weak bases
generally have much higher aqueous
solubility than the free acid or base.
- The dissolution rate of a weakly acidic drug in
gastric fluid (pH 1 – 3.5) will be relatively low.
- If the pH in the diffusion layer increased, the
solubility, Cs, of the acidic drug in this layer, and
hence its dissolution rate in gastric fluids would be
increased.
139. C. Drug Dissolution (cont.):
- The pH of the diffusion layer would be increased if the
chemical nature of the weakly acidic drug was changed
from that of the free acid to a basic salt (the sodium or
potassium form of the free acid.)
- The pH of the diffusion layer would be higher (5-6) than
the low bulk pH (1-3.5) of the gastric fluids because of the
neutralizing action of the strong (Na+
, K+
) ions present in
the diffusion layer.
- The drug particles will dissolve at a faster rate and diffuse
out of the diffusion layer into the bulk of the gastric fluid,
where a lower bulk pH.
140. C. Drug Dissolution (cont.):
- Thus the free acid form of the drug in solution, will
precipitate out , leaving a saturated solution of free acid in
gastric fluid.
This precipitated free acid will be in the form of:
- very fine,
- non-ionized,
- wetted particles which have a very large surface area in
contact with gastric fluids, facilitating rapid redissolution
when additional gastric fluid is available.
142. Drug Dissolution (cont.):
- One example is the dissolution and bioavailability profiles of
Penicillin V with various salts.
These results might support the use of the benzathine or procaine salts for
IM depot use and the potassium salt for better absorption orally.
143. Drug Dissolution (cont.):
E- Crystal form:
1- Polymorphism:
- Some drugs exist in a number of crystal forms or
polymorphs. These different forms may have different
solubility properties and thus different dissolution
characteristics.
- Chloramphenicol palmitate is one example which exists in
three crystalline forms A, B and C.
A is the stable polymorph
B is the metastable polymorph (more soluble)
C is the unstable polymorph
- The plasma profiles of chloramphenicol from oral
suspensions containing different proportions of
144. Drug Dissolution (cont.):
Polymorphic forms A and B were investigated.
-The extent of absorption of
Chloramphnicol increases as the
Proportion of the polymorphic form
B is increased in each suspension.
This is attributed to the more rapid
Dissolution of the metastable
Polymorphic form B.
- Shelf-life could be a problem as the more soluble (less
stable) form may transform into the less soluble form
(more stable).
145. Drug Dissolution (cont.):
2- Amorphous solid:
- The amorphous form dissolves more rapidly than the
corresponding crystalline form.
- The more soluble and rapidly dissolving amorphous form
of novobiocin antibiotic was readily absorbed following
oral administration of an aqueous suspension to humans.
However, the less soluble and slower-dissolving
crystalline form of novobiocin was not absorbed
(therapeutically ineffective).
- The amorphous form of novobiocin slowly converts to the
more stable crystalline form, with loss of therapeutic
effectiveness.
146. Drug Dissolution (cont.):
3- Solvates:
Solvates: If the drug is able to associate with solvent
molecules to produce crystalline forms known as solvates.
Hydrates: drug associates with water molecules.
- The greater the solvation of the crystal, the lower are the
solubility and dissolution rate in a solvent identical to the
solvation molecules.
147. Drug Dissolution (cont.):
- The faster-dissolving anhydrous form of ampicillin was
absorbed to a greater extent from both hard gelatin
capsules and an aqueous suspension than was the slower-
dissolving trihydrate form.
148. D- Drug stability and hydrolysis in
GIT:- Drugs that are susceptible to acidic or enzymatic
hydrolysis in the GIT, suffer from reduced bioavailability.
- How to protect drugs (erythromycin) from degradation in
gastric fluid ??
1- Preparing enteric coated tablets containing the free base
of erythromycin. The enteric coating resists gastric fluid
but disrupts or dissolves at the less acid pH range of the
small intestine.
2- The administration of chemical derivatives of the parent
drug. These prodrugs (erythromycin stearate) exhibit
limited solubility in gastric fluid, but liberate the drug in
the small intestine to be absorbed.
149. E- Complexation:
- Complexation of a drug may occur within the dosage form
and/or in the gastrointestinal fluids, and can be benefecial
or deterimental to absorption.
1- Intestinal mucosa (mucin) + Streptomycin = poorly
absorbed complex
2- Calcium + Tetracycline = poorly absorbed complex
(Food-drug interaction)
3- Carboxyl methylcellulose (CMC) + Amphetamine =
poorly absorbed complex (tablet additive – drug
interaction)
4- Lipid soluble drug + water soluble complexing agent =
well-absorbed water soluble complex ( cyclodextrin)
150. F- Adsorption:
- Certain insoluble susbstances may adsorbed co-
administrated drugs leading to poor absorption.
Charcoal (antidote in drug intoxication).
Kaolin (antidiarrhoeal mixtures)
Talc (in tablets as glidant)
151. Absorption
Main factors affecting oral absorption:
I Physiological factors.
II Physical-chemical factors.
III Formulation factors.
I Physiological factors affecting oral absorption:
1- Membrane physiology.
2- Passage of drugs across membranes.
3- Gastrointestinal physiology.
I. Characteristics of GIT physiology and drug absorption
II. Gastric emptying time and motility
III. Effect of food on drug absorption
152. III Formulation Factors Affecting Oral
Absorption:
- The role of the drug formulation in the delivery of drug
to the site of action should not be ignored.
- Since a drug must be in solution to be absorbed
efficiently from the G-I tract, you may expect the
bioavailability of a drug to decrease in the order
solution > suspension > capsule > tablet > coated
tablet.
A. Solution dosage forms:
- In most cases absorption from an oral solution is rapid and
complete, compared with administration in any other
oral dosage form.
153. III Formulation Factors Affecting Oral
Absorption (Cont.):
- Some drugs which are poorly soluble in water may
be:
1- dissolved in mixed water/alcohol or glycerol
solvents (cosolvency),
2- given in the form of a salt (in case of acidic drugs)
3- An oily emulsion or soft gelatin capsules have
been used for some compounds with lower
aqueous solubility to produce improved
bioavailability.
154. III Formulation Factors Affecting Oral
Absorption (Cont.):
B. Suspension dosage forms:
- A well formulated suspension is second to a
solution in terms of superior bioavailability.
- A suspension of a finely divided powder will
maximize the potential for rapid dissolution.
- A good correlation can be seen for particle size
and absorption rate.
- The addition of a surface active agent will improve
the absorption of very fine particle size
suspensions.
155. III Formulation Factors Affecting Oral
Absorption (Cont.):
Absorption of drugs from aqueous suspensions
156. III Formulation Factors Affecting Oral
Absorption (Cont.):
C. Capsule dosage forms:
- The hard gelatin shell should disrupt rapidly and allow the
contents to be mixed with the G-I tract contents.
- If a drug is hydrophobic a dispersing agent should be
added to the capsule formulation. These diluents will work
to disperse the powder, minimize aggregation and
maximize the surface area of the powder.
- Tightly packed capsules may have reduced dissolution and
bioavailability.
158. III Formulation Factors Affecting Oral
Absorption (Cont.):
- The tablet is the most commonly used oral dosage form.
- It is also quite complex in nature.
1-Ingredients
Drug : may be poorly soluble, hydrophobic
Lubricant : usually quite hydrophobic
Granulating agent : tends to stick the ingredients together
Filler: may interact with the drug, etc., should be water
soluble
Wetting agent : helps the penetration of water into the
tablet
Disintegration agent: helps to break the tablet apart
159. III Formulation Factors Affecting Oral
Absorption (Cont.):
- Coated tablets are used to mask an unpleasant taste, to
protect the tablet ingredients during storage, or to improve
the tablets appearance.
This coating can add another barrier between the solid drug
and drug in solution. This barrier must break down
quickly or it may hinder a drug's bioavailability.
- Sustained release tablet
Another form of coating is enteric coated tablets which are
coated with a material which will dissolve in the intestine
but remain intact in the stomach.
160. DRUG DISTRIBUTION
Factors Affecting Drug Distribution:
1. Blood Flow
2. Capillary permeability; determined by:
capillary structure. In the brain, we also
have the Blood Brain Barrier (BBB) - barrier
between brain tissues and circulating blood
chemical nature of the drug
3. Binding of drugs to plasma proteins
161. Plasma Albumin is the major
drug binding protein.
“Bound drugs are
pharmacologically inactive; only
the free, unbound drug can act
on the target sites in the tissues,
elicit a biologic response, and be
available to the process of
elimination”
164. How do we determine
the Vd in 4 scenarios?
Apparent Volume of Distribution or
Vd
~ The volume into w/c drugs
distribute.
165. Apparent Volume of Distribution
1. Absence of Elimination. Assuming that the
drug distributes and is not eliminated.
Vd = D D = the total amount of drug in
the body
C C = the plasma concentration of the
drug
Ex. If 25mg of a drug are administered and the
plasma conc is 1mg/L, what will be its volume
of distribution?
Vd = 25mg
1mg/L
Vd = 25L
166. Apparent Volume of Distribution
2. Elimination is present. The rate at w/c
the drug is eliminated is usually
proportional to the concentration of drug, C.
If C is equal to 1mg/mL, it is the same
amount of drug eliminated in the body.
Drug concentrations in serum after a single
injection of drug at time = 0. Assume that
the drug distributes and is subsequently
eliminated.
168. Apparent Volume of Distribution
3. Distribution is instantaneous. Assuming that the
elimination process began at the time of injection
and continued throughout the distribution phase.
C, plasma concentration of the drug, can be extrapolated back to time
zero (time of injection) to determine C0.
C0 = the concentration of drug that would have been achieved if the
distribution phase had occurred instantly.
Ex. If 10mg of drug are injected into a patient and
the plasma concentration is extrapolated to time
zero, the concentration is C0 = 1mg/L, what will be
its volume of distribution? Vd = 10mg
1mg/L Vd = 10L
170. Apparent Volume of Distribution
4. Uneven distribution between compartments.
Ex. Assume the arrhythmia of a cardiac patient is not well
controlled due to inadequate plasma levels of digitalis.
Suppose the concentration of drug in the plasma is C1 and
the desired level of digitalis is a higher concentration, C2.
The clinician needs to know how much additional drug
should be administered to bring the circulating level of the
drug from C1 to C2:
(Vd)(C1) = amount of drug initially in the body
(Vd)(C2) = amount of drug in the body needed to achieve the
desired plasma concentration.
The difference between the two values is the additional
dosage needed, w/c equals Vd(C2 - C1).
171. Effect of a large Vd on the half-life of a
drug:
“If the Vd for a drug is large, most of the
drug is in the extraplasmic space and is
unavailable to the excretory organs.
Therefore, any factor that increases the
volume of distribution can lead to an
increase in the half-life and extend the
duration of action of the drug.”
173. Kinetics of Metabolism
1. First-order Kinetics – a constant fraction of drug
is metabolized per unit time.
The metabolic transformation of drugs is catalyzed
by enzymes, and most of the reactions obey
Michaelis-Menten kinetics.
“The rate of drug metabolism is directly proportional
to the concentration of free drug”.
174. Kinetics of Metabolism
2. Zero-order Kinetics – a constant amount of drug is
metabolized per unit time.
“The enzyme is saturated by a high free-drug
concentration, and the rate of drug metabolism
remains constant over time.”
176. First order kinetics means the amount of
excretion depends on the amount of drug
present.
Zero order kinetics means that the amount
of excretion is independent of the amount of
drug present.
178. ELIMINATION
Most important route in removal of a drug from
the body is through the kidney (major organ of
excretion) into the urine. Other routes include the
bile, intestine, lung or milk in nursing mothers.
181. BASIC TERMINOLOGIES
Receptor a specific molecule, usu. a protein
that interacts with a specific chemical that
then causes a change in the specific molecule
causing a change in regulatory function.
Ligand Any substance (e.g. hormone, drug, etc.)
that binds specifically and reversibly to another
chemical entity to form a larger complex; a signal
triggering molecule, binding to a site on a target
protein.
may function as agonist or antagonist.
From Latin ligandus, rootword is ligare
meaning ‘to bind’.
182. Receptors as targets for drugs:
over 10,000 different proteins in the body which
means there are potentially over 10,000 different
targets
Different tissues express different proteins so that
drugs can target specific proteins on the heart,
blood vessels, bronchioles etc.
Proteins have important functions in the body so
they make worthwhile targets
183. - lipid structure
- resistant to the entry
of most non-lipid
substances, including
proteins and ions
Some drugs can cross the membrane and bind to
internal cell receptors whilst others cannot, therefore,
those that cannot bind to receptors on the outside of
the cell in order to exert their effect on the cell.
Regions of the Cell:
Intracellular region - means
inside the cell.
Extracellular region - means
outside of the cell
184. Drug Receptor Interactions
Receptors have a specific shape that allows the messenger to
dock with that receptor, rather like a lock that allows only one
key to open it. In addition to shape, receptors and messengers
bind via tiny electro-magnetic forces such as van de Waals
forces and hydrogen bonds.
185. Major Receptor Families
1. Ligand-gated ion
channels - these involves
the movement of ions across
cell membrane through
opening of an ion channel.
These channels can open or
close, allowing control over
the movement of ions.
186. For example, acetylcholine binding to a
cholinergic receptor in the neuromuscular
junction opens sodium channels and
promotes contraction in the muscle cell.
189. 3. Enzyme-linked receptors
also known as a catalytic receptor - is a
transmembrane receptor, where the binding of an
extracellular ligand causes enzymatic activity on
the intracellular side.
191. Some characteristics of Receptors
SPARE RECEPTORS
- Ability to amplify signal duration and intensity
- Exhibited by Insulin receptors
Has an immense functional
reserve that ensures adequate
amounts of glucose enter the
cell
- Only 5 to 10% of the total beta-
adrenoceptors of the heart are spare.
“Most receptors must be occupied to obtain
maximal contractility”
192. Desensitization of
Receptors
Repeated or continuous
administration of an
agonist/antagonist may lead to
changes in the responsiveness
of the receptors.
TACHYPHYLAXIS
E.g. Voltage-gated
channel receptor,
require a finite time
(rest period)
following
stimulation before
they can be
activated again.
193. Importance of the Receptor
Concept
Most Drugs interact with receptors
that will determine selective
therapeutic and toxic effects of the
drug.
Receptors largely determine the
quantitative relations bet. dose of a
drug and its pharmacologic effect.
194. AGONISM
Agonist – any drug (a ligand) that binds to a receptor and
activates the receptor.
Once the agonist comes in contact with a protein
receptor, there’ll be a chemical reaction that will occur
causing a change inside the cell. This chemical rxn is a
natural process by the body.
In many receptors, agonist leaving the binding site
deactivates the receptor. In other receptors, agonist
permanently activates the receptor until that receptor
has been broken down by the body.
196. Types of Pharmacologic Antagonist
Competitive (reversible) antagonist - it fits into the
lock but doesn’t activate it. It competes with the
agonist at the agonist binding site.
Ex. Atropine is the competitive antagonist of
Acetylcholine at the muscarinic receptors.
197. Non Competitive (irreversible)
antagonist – any antagonist that
binds to a site on the receptor
other than the agonist binding
site.
Ex. ketamine is a non-competitive
antagonist at the NMDA-
glutamate receptor
198. Chemical Antagonist
any drug that binds directly to an agonist and deactivates
the agonist.
Common ex. Protamine is the chemical antagonist of
Heparin, a blood thinner.
Physiological/Functional
Antagonist
a drug that opposes or reverses the effect of an
agonist by binding to a different receptor and
producing the opposite physiological effects.
Common ex. Effect of Adrenaline (epinephrine)
during anaphylactic shock.
199. Drug Effectiveness
Dose-response (DR) curve:
Depicts the relation between
drug dose and magnitude of
drug effect
Drugs can have more than
one effect
Drugs vary in effectiveness
Different sites of action
Different affinities for receptors
The effectiveness of a drug is
considered relative to its
safety (therapeutic index)
201. Measure of the amount of drug necessary to
produce an effect of a given magnitude
EFFICACY
The ability of a drug to illicit a physiologic
response when it interacts with a receptor.
POTENCY
205. QUANTAL DOSE-RESPONSE
RELATIONSHIP
Quantal D-R Curves plot the percentage of a
population responding to a specified drug effect
versus dose or log dose.
They permit estimations of the median effective
dose (ED50)
(e.g., effective dose in 50% of a population)
206.
207.
208. This is a figure of two
different dose response
curves. You can obtain a
different dose response
curve for any system that
the drug effects. When
you vary the drug, this is
the Independent
variable, what you are
measuring is the % of
individuals responding
to the drug. Here we see
the drugs effects on
hypnosis and death.
Notice that the effective
dose for 50 % of the
people is 100 mg and if
you double the dose to
200 mg then 1 % of your
subjects die. Thus, if you
want to use this drug to
hypnotize 99 % of your
subjects, in the process
you will kill 2-3 % of
your subjects.
This is a figure of two
different dose response
curves. You can obtain a
different dose response
curve for any system that
the drug effects. When
you vary the drug, this is
the Independent
variable, what you are
measuring is the % of
individuals responding
to the drug. Here we see
the drugs effects on
hypnosis and death.
Notice that the effective
dose for 50 % of the
people is 100 mg and if
you double the dose to
200 mg then 1 % of your
subjects die. Thus, if you
want to use this drug to
hypnotize 99 % of your
subjects, in the process
you will kill 2-3 % of
your subjects.
209.
210. Drug Safety and Effectiveness
Not all people respond to a similar dose of a
drug in the exact same manner, this variability
is based upon individual differences and is
associated with toxicity. This variability is
thought to be caused by:
Pharmacokinetic factors contribute to differing
concentrations of the drug at the target area.
Pharmacodynamic factors contribute to differing
physiological responses to the same drug
concentration.
Unusual, idiosyncratic, genetically determined or
allergic, immunologically sensitized responses.
211. Definitions you should know
Pharmacokinetics, intravascular,extravascular
Absorption ; process by which a drug proceeds from
the site of administration to the site of measurement
within the body.
Disposition ; all the processes that occur subsequent to
the absorption of a drug
Distribution ; reversible transfer of a drug to and
from the site of measurement.
Metabolism; irreversible conversion to another
chemical species.
Excretion; irreversible loss of the chemically
unchanged drug
212. Definitions you should know
Accumulation; the increase of drug concentration in blood
and tissue upon multiple dosing until steady state is
reached
Steady state; the level of drug accumulation in blood and
tissue upon multiple dosing when input and output are at
equilibrium .
Biophase ; the actual site of action of drug in the body.
A receptor; a site in the biophase to which drug molecules
can be bound
A compartment in pharmacokinetics; an entity which can
be described by adefinite volume and concentration of drug
contained in that volume. In pharmacokinetics ,
experimental data are explained by fitting them to
compartmental models.
213. Definitions you should know
Central compartment; the sum of all body regions( organs
and tissue) in which the drug concentration is in
instantaneous equilibrium with that in blood or plasma.
The blood or plasma is always part of the central
compartment
Peripheral compartment; the sum of all body regions to
which a drug is eventually distributes but is not in
instantaneous equilibrium.
Feathering ; refers to a graphical method for separation of
exponents such as separating the absorption rate constant
from the elimination rate constant. ( residual method)
Biliary recycling; the phenomenon that drugs emptied via
bile in to the small intestine can be reabsorbed from the
intestinal lumen in to systemic circulation.
214. Definitions you should know
Apparent partition coefficient; the ratio of the concentration
at equilibrium between a lipoid phase (n, octane) and an
aqueous phase ( buffer ph 7.4).
Area under the curve; the integral of drug level over time
from zero to infinity, and is a measure of the quantity of drug
absorbed in the body.
Clearance rate; the volume of blood in ml which is completely
cleared of the drug per unit time (minute) by urinary
excretion or metabolism.
Renal clearance; the hypothetical plasma volume (volume of
plasma volume (volume of of unmetabolized drug which is
cleared in one minute via the kidney.
Hepatic clearance; the hypothetical plasma volume (volume
of distribution) in ml of the metabolized drug which is cleared
in one minute via the liver
Notes de l'éditeur
Upper GI: pharynx, esophagus, stomach.
Lower GI: small intestine (duodenum, jejunum, ileum) and large intestine (cecum, colon, rectum, anal canal)
How they work:
The colon – This is the body’s ‘sewer’: the main place where wastes are removed from you. Anything that you ingest that cannot be converted into useful stuff to fuel the body will be dealt with in main by the colon.
The lungs – Some wastes come out, as gas, through the lungs (for example carbon dioxide).
The skin – This is the largest organ in the body. Toxins come out through our skin when we sweat – the average toxic loss each day is 2 pounds! When the body has more toxins than it can handle it will try to push these out through the skin.
The lymph – This intricate web extends through the whole body. The lymph system takes waste from your cells and puts it into the blood stream so it can be dealt with by the liver or the kidneys.
The kidneys – These filter our blood of waste at an astounding rate of 150 to 180 litres every 24 hours.
The liver – The liver is not one of the five ‘elimination organs’ but it plays a vital role in the removal of toxins in the body by filtering our blood. If it is overworked the toxins build up in the blood stream, making us feel lousy and causing immune system dysfunction and disease.
Lumen – inside of GIT
Perlingual – administration through the tongue
OTHER Routes
Inhalation – used for drugs that are gases (e.g., some anesthetics) or those that can be dispersed in an aerosol. Commonly used for patients with respiratory complaints (asthma or chronic obstructive pulmonary disease)
Intranasal – administering drugs directly into the nose.
Intrathecal/intraventricular - into the spinal canal, most commonly used for spinal anesthesia and chemotherapy
Topical - local effect, substance is applied directly where its action is desired. Sometimes, however, the term topical is defined as applied to a localized area of the body or to the surface of a body part or through mucous membranes in the body. Such as,
d.1 epicutaneous (application onto the skin), e.g. allergy testing, typical local anesthesia
d.2 inhalational, e.g. asthma medications
d.3 enema, e.g. contrast media for imaging of the bowel
d.4 eye drops (onto the conjunctiva), e.g. antibiotics for conjunctivitis
d.5 ear drops - such as antibiotics and corticosteroids for otitis externa
Transdermal - diffusion of drugs through the intact skin for systemic rather than topical distribution, e.g. transdermal patches such as once a week contraceptive patch (Ortho Evra), nicotine patches for treatment of addiction and nitroglycerine for treatment of angina pectoris
Rectal - into the rectum. 50% of the drainage of the rectal region bypasses the portal circulation thus, biotransformation of drugs by the liver is minimized.
An enema (/ˈɛnəmə/; plural enemata or enemas) is the procedure of introducing liquids into the rectum and colon via the anus. The increasing volume of the liquid causes rapid expansion of the lower intestinal tract, often resulting in very uncomfortable bloating, cramping, powerful peristalsis, a feeling of extreme urgency and complete evacuation of the lower intestinal tract. An enema has the advantage over any laxative in its speed and certainty of action, and some people prefer it for this reason.
Lattice synonym: grid
Agitation produces convection, moving bulk groups of molecules around. As something dissolves, the concentration of solute rises in its vicinity, slowing the rate. Agitation removes solute-laden solvent in the vicinity of the solid, and brings in fresh, low-concentration regions of solute.
portal circulation refers to the circulation of the blood from the small intestine to the liver, via the portal vein. Blood flow to the liver is unique in that it receives oxygenated and de-oxygenated blood. Blood passes from branches of the portal vein through cavities between "plates" of hepetocytes called sinusoids. Blood also flows from branches of the hepatic artery and mixes into the sinusoids to supply the hepatocytes with oxygen. This mixture percolates through the sinusoids and collects in a central vein which drain into the hepatic vein. The hepatic vein subsequently drains into the inferior vena cava.
Definition of Percutaneous Route of Administration:Administration of a drug by the way of absorption through the skin, usually for systemic action. The route allows sustained therapeutic plasma drug levels and avoids first pass effect. Simplicity of administration tends to result in high patient compliance.
Noyes Whitney Equation based from Fick’s first law of diffusion
