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Akash Mahadev Iyer
S4 M Sc Biochemistry
Department of biochemistry
Karyavattom campus
University of Kerala
How does the human body act on the drugs?
 The interactions between a drug and the body are conveniently divided into two
classes.
 Pharmacokinetic processes
 Pharmacodynamic processes
• Pharmaco- Greek word (pharmackon) for “drug,”, and kinetics from the Greek
word (kinetikos) for “moving,”.
• Pharmacokinetics (PK) is the study of drug movement into, around, and out of
the body - drug absorption, distribution, and elimination (metabolism and
excretion) (ADME).
1. Absorption: from the site of administration permits entry of the drug (either
directly or indirectly) into plasma.
2. Distribution: the drug may then reversibly leave the bloodstream and
distribute into the interstitial and intracellular fluids.
3. Metabolism: the drug may be biotransformed by metabolism by the liver or
other tissues.
4. Elimination: the drug and its metabolites are eliminated from the body in
urine, bile, or feces.
Pharmacokinetics refers to what the body does to a drug, whereas
pharmacodynamics describes what the drug does to the body.
Pharmacokinetics
• Absorption is the transfer of a drug from the site of administration to the bloodstream.
• The Plasma Membrane Is Selectively Permeable
• Passive diffusion dominates transmembrane movement of most drugs.
 Active processes play a role in the movement of many drugs, whose molecules are too large
to diffuse readily.
CARRIER MEDIATED
OUT OUTIN IN
Used to transport drugs of large size across the cell membrane.
Endocytosis -engulfment of a drug by the cell membrane and transport into the cell by
pinching off the drug filled vesicle.
Uptake of extracellular material by its inclusion in a vesicle formed by invagination of the
Plasma membrane
Exocytosis -reverse of endocytosis, the fusion of intracellular vesicle with plasma membrane ,
releasing the vesicle contents to extracellular space
Cells use exocytosis to secrete substances out of the cell.
Factors influencing rate of absorption
 Route of administration- influences bioavailability
 IV administration- immediate and complete absorption.
 Extravascularly administered - carried through various barriers to reach the blood
circulation and their site of action.
 Concentration of drug- Increase in conc. increases rate of absorption
 pH – influences the lipid solubility
 Molecular size: The smaller in size-----more absorption
 Surface area - The more absorptive surface area, the more absorption.
 Brush borders of the intestine -1000-fold SA to that of the stomach, - Hence EFFICIENT
ABSORPTION….
 Blood Flow- The intestines receive much more blood flow than the stomach, so absorption
from the intestine is favored over the stomach.
 Contact time at the absorption surface: If a drug moves through the GI tract very quickly
(in severe diarrhea), it is not well absorbed.
 Food in the stomach -dilutes the drug and slows gastric emptying.- drug taken with a meal is
generally absorbed more slowly
Expression of P-glycoprotein
 P-glycoprotein is a TM transporter
 Phosphorylated protein of MDR family of ABCs transporters,
 Expressed in - liver, kidneys, placenta, intestines etc.
 Involved in transportation of drugs from tissues to blood-“pumps” drugs out of the
cells.
 Thus, in areas of high expression, P-glycoprotein reduces drug absorption
Effect of pH on drug absorption
• Most drugs are weak organic acids or bases, so they undergo
ionization
• Ionization of drugs reduces its ability to permeate membranes-
(REDUCES LIPOPHILICITY…)
A drug is present in solution as both the
 Lipid-soluble, diffusible, non-ionized form and
 The ionized form - lipid insoluble and poorly diffusible across a
membrane.
 Common ionizable groups -COOH, -NH2
o (1º, 2º, 3º, and 4º amines hold a permanent +ve charge ).
• The degree of ionization of a drug is determined by the surrounding pH
and pKa of the drug
A drug passes through membranes more readily if it is uncharged
 A drug passes through membranes more readily if it is uncharged. Thus,
for a weak acid, the uncharged, protonated HA can permeate through
membranes, and A− cannot.
 For a weak base, the uncharged form B penetrates through the cell
membrane, but the protonated form BH+ does not. Therefore, the
effective concentration of the permeable form of each drug at its
absorption site is determined by the relative concentrations of the
charged and uncharged forms. The ratio between the two forms is, in
turn, determined by the pH at the site of absorption and by the strength
of the weak acid or base, which is represented by the ionization
constant, pKa.
 [Note: The pKa is a measure of the strength of the interaction of a
compound with a proton.
 The lower the pKa of a drug, the more acidic it is. Conversely, the higher
the pKa, the more basic is the drug.] Distribution equilibrium is achieved
when the permeable form of a drug achieves an equal concentration in
all body water spaces.
pH
 pH is simply a measure of the [H+] concentration in a given
solution
 pKa is defined as the pH were a drug exists as 50% ionized
and 50% unionized. If pKa - pH = 0, then 50% of drug is
ionized and 50% is unionized.
 Before explaining the ionization and absorption processes of
these drugs, it is important to understand the equilibrium
step for the non-ionized (un-dissociated) and ionized
(dissociated) forms. This equilibrium is described by the
following equation, commonly known as the Henderson–
Hasselbalch equation, and is written as follows:
Ionization of Weak Acids and Weak Bases;
Henderson-Hasselbalch Equation
 A weak acid - neutral molecule that can reversibly dissociate into an anion and a
proton (a hydrogen ion).
 A weak base; neutral molecule that can reversibly dissociated into a cation and a
proton
HA H+ + A-
Ka
B + H+BH+
Kb
pKa=pH+log(HA/A-)
pKb=pH+log(BH+/B)
Aspirin is reasonably absorbed
from stomach
pKa of Aspirin= 3.4 (50 % HA and 50% A- ) at
pH 3.4)
If pH < pKa – drug is unionised (High
H+ in surrounding envt) -If the pH is
lower than the pKa, then the
compound will be protonated.
If pH > pKa – drug is ionised - If the
pH is higher than the pKa, then the
compound will be deprotonated.
Pharmacokinetics
 Bioavailability is defined as the fraction of unchanged drug reaching the systemic circulation,
following administration by any route.
 Expressed as percentage.
 If a 1 gram dose of a drug is administered by mouth, and half of that reaches the systemic
circulation, the drug is 50% bioavailable.
Determination of bioavailability:
 Bioavailability is determined by comparing plasma levels of a drug after a particular route of
administration (for eg; oral administration) with levels achieved by IV administration.
F =
AUC (oral)
AUC (iv)
x 100
 After IV administration, 100% of the drug rapidly enters the
circulation. When the drug is given orally, only part of the
administered dose appears in the plasma.
 By plotting plasma concentrations of the drug versus time, the area
under the curve (AUC) can be measured.
 The total AUC reflects the extent of absorption of the drug.
Bioavailability of a drug given orally is the ratio of the AUC following
oral administration to the AUC following IV
 Need for Bioavailability studies- To establish important
pharmacokinetic parameters, dosage regimen, dose labelling
• Also explains why the same dose may cause a therapeutic effect by
one route and same dose may cause a toxic effect by another route.
Pharmacokinetics
Increased risk of resistance
Increased risk of side effects
Missed dose/ late dose
AUC; total amount of active substance which was in the bloodstream over the
period studied
The AUC can be derived from either single-dose studies (left) or multiple-dose measurements (right)
MEC/ Minimum Therapeutic Dose ; Minimum conc. of drug required by the body to
produce therapeutic effect
MSC/ Minimum Toxic Dose ; The conc. of drug in plasma above which toxic
effects are seen
Therapeutic range ; The range b/w Minimum Toxic Dose and Minimum Therapeutic
Dose
 The elimination of drug that occurs after administration but before it enters the systemic
circulation (eg, during passage through the gut wall, portal circulation, or liver for an orally
administered drug)
 Reduces amount of unchanged drug entering the systemic circulation.
• All orally administered drugs are exposed to drug metabolizing enzymes in the intestinal wall
and liver.
This refers to metabolism of a drug during its passage from the site of absorption into the systemic circulation.
 Route of administration
 First-pass hepatic metabolism
 More than 90% of nitroglycerin is cleared during first-pass metabolism. Hence, it is primarily
administered via the sublingual or transdermal route.
• Drugs with high first-pass metabolism should be given in doses sufficient to ensure that
enough active drug reaches the desired site of action,
• Drugs such as propranolol and nitrates undergo significant hepatic metabolism during a
single passage through the liver
 Solubility of the drug:
 Very hydrophilic drugs are poorly absorbed because of their inability to cross lipid-rich cell
membranes.
 Drugs that are extremely lipophilic are also poorly absorbed, because they are totally
insoluble in aqueous body fluids and, therefore, cannot gain access to the surface of cells.
• When a dose of a drug is given intravenously, the whole drug
reaches in circulation and the bioavailability is equal to one/
100 %.
• When a drug is administered through other route (such as
orally) bioavailability maybe less than one / < 100%
May be because of :
• Incomplete absorption
• Solubility of drug
• After oral administration, a drug maybe incompletely absorbed
because of too hydrophilic that cannot pass through the lipid
cell membrane, or too lipophilic that the drug is not soluble
enough to cross the water layer adjacent to the cell.
Chemical instability:
 Penicillin G -unstable in gastric pH.
 Insulin- destroyed in the GI tract by degradative enzymes.
Nature of the drug formulation:
 Drug absorption may be altered by particle size, salt form, crystal
polymorphism, enteric coatings, and the presence of excipients (such as
binders and dispersing agents) can influence the ease of dissolution and,
therefore, alter the rate of absorption
Distribution
 Drug distribution is the process by which a drug reversibly leaves the
bloodstream and enters the interstitium (extracellular fluid) and the tissues.
 No absorption process for IV administered drugs, is directly distributed, during
which the drug rapidly leaves the circulation and enters the tissues
• Passive Process, -driving force is the Conc. Gradient b/w blood and Extra-
vascular Tissues. - occurs until equilibrium is established.
• Distribution is not uniform throughout the body -different tissues receive the
drug from plasma at different rates and to different extents.
• Drug concentration in blood or plasma depends on the amount of drug present
in the body as well as how extensively it is distributed. The latter can be
assessed from its Vd.
Factors affecting the rate of distribution
 Blood flow; Greater Blood flow to “vessel-rich organs” (brain, liver, and kidney) than
skeletal muscles.
 The most vitally important organs of the body receive the greatest supply of blood. These organs
include the brain, liver, and kidneys. Skeletal muscle and bone receive less blood, and adipose tissue
(fat) receives the least.
 Blood flow to the “vessel-rich organs” (brain, liver, and kidney) is greater than that to the
skeletal muscles.
• If blood flow were the only factor affecting distribution, it would be reasonable to expect that high
concentrations of administered medications would always appear in the brain and liver.
 Capillary permeability is determined by capillary structure and by the chemical nature of the
drug.
 In the liver and spleen, a significant portion of the basement membrane is exposed due to
large, discontinuous capillaries through which large plasma proteins can pass
 In the brain, the capillary structure is continuous
 To enter the brain, drugs must pass through the endothelial cells of the CNS capillaries or be
activley transported
Bone can become a reservoir for the slow release of toxic
agents such as lead or radium
 To enter the brain, drugs must pass through the endothelial
cells of the CNS capillaries or be actively transported.
 Lipid -soluble drugs readily penetrate the CNS because they
dissolve in the endothelial cell membrane. Small and highly
fat-soluble anesthetic gases quickly and easily penetrate the
brain to cause anesthesia,
 Ionized or polar drugs generally fail to enter the CNS
because they cannot pass through the endothelial cells
These closely juxtaposed cells form tight junctions that
constitute the blood–brain barrier.
 Capillary permeability
 Drugs molecular weight (< 500 to 600 Da) easily cross the capillary
membrane to penetrate into the extracellular fluids (except in CNS)
because junctions between the capillary endothelial cells are not
tight
 Lipophilicity
 Water-soluble molecules and ions of size below 50 daltons enter the
cell -aqueous filled channels,
 Larger size - specialized transport system.
 Different drugs binding to different proteins
 Acidic drugs, Albumins Ex- Bilirubin, Bile acids, Fatty acids, Vitamin
C, Salicylates, Sulfonamides, Barbiturates, Probenecid,
Phenylbutazone, Penicilins, Tetracyclines etc
 Basic drugs Globulins Ex- Adenosine, Quinacrine, Quinine,
Streptomycin,Chloramphenicol, Digitoxin, Ouabain, Coumarin
 Bone
 The tetracycline antibiotics (and other divalent metal-ion chelating agents) and heavy
metals may accumulate in bone by adsorption onto the bone crystal surface
 Fat as a Reservoir
 Many lipid-soluble drugs are stored in the neutral fat.
 Fat - stable reservoir -it has a relatively low blood flow.
When a drug enters the body, it exists in:
I. Free form
• Free forms are metabolized and excreted -they can cross the glomerular membrane.
• Therapeutically active.
II. Bound form
• Not metabolized or excreted and do not have therapeutic or toxic effect.
• When the free form is used up, drug is released from the reservoirs.
Thus both forms exist in equilibrium.
Significance:
• Bound form acts as a reservoir, providing free form when required
Volume of distribution
 A direct measure of extent of distribution of a drug in rest of body compared to
plasma
 Vd, is defined as the fluid volume that is required to contain the entire drug in the body at
the same concentration measured in the plasma.
 Lipid insoluble / highly protein bound drug– restricted to vascular compartment – low Vd
 Drugs sequestered in other tissues – large Vd
The human body is not a glass beaker !!!!
 Drugs distribute in and out of different tissue compartments.
 The human body is (~70%) water, So, we can think of the body as containers with water:
 If Vd = 7.4 L or less –drug is confined to the plasma.
This may occur for two reason
 The molecule is too large to leave this compartment.
 The molecule binds preferably to plasma proteins (e.g. to albumin) and much less to tissue
proteins.
 Some drugs cannot enter cells because of their low lipid solubility. These drugs are
distributed throughout the body water in the extracellular compartment and have a relatively
small Vd (12-20 L).
 If Vd >42 L - drug is thought to be distributed to all tissues in the body, especially the fatty
tissue.
 If Vd = >10,000 L! -most of the drug is in the tissues, and very little is in the plasma
circulation
Dose or Amount of drug in body / drug concentrationVolume of distribution =
 Larger Vd, the more likely that the drug is
found in the tissues of the body. Drugs that
accumulate in organs either by active transport
or by specific binding to tissue molecules.
 Smaller Vd, the more likely that the drug is
found in circulation
• Patients with edema, ascites, or pleural
effusions offer a larger volume of distribution-
Due to increase in total water
.
Skeletal muscle,
heart
Digoxin, Emetine (bound to muscle proteins).
Liver Chloroquine, Tetracyclines, Emetine, Digoxin.
Kidney Digoxin, Chloroquine, Emetine.
Thyroid Iodine.
Brain Chlorpromazine, Acetazolamide, Isoniazid.
Retina Chloroquine (bound to nucleoproteins).
Iris Ephedrine, Atropine (bound to melanin).
Bone and teeth Tetracyclines, Heavy Metals (bound to Mucopolysaccharides of
connective tissue), Bisphosphonates (bound to Hydroxyapatite)
Adipose tissue Thiopentone, Ether, Minocycline, Phenoxybenzamine, DDT
dissolve in neutral fat due to high lipid-solubility; remain
stored due to poor blood supply of fat.
Drug VD Comments
Warfarin 8L Reflects a high degree of
plasma protein binding.
Theophylline 30L Represents distribution in
total body water.
Chloroquine 15000L Highly lipophilic
molecules which
partitions into body fat
NXY-059 8L Highly-charged
hydrophilic molecule.
 Once a drug enters the body, it has the potential to distribute into any one of the
three functionally distinct compartments of body water or to become sequestered in
a cellular site.
 Plasma compartment:
 Extracellular fluid
 Total body water
Distribution into the water compartments in the body:
Metabolism
 Biotransformation
 Increases hydrophilicity
Primary site of drug metabolism – liver
Other sites; Kidney, intestine, lungs and plasma.
 Chemical alteration of the drug in the body.
 Converts non polar (lipid-soluble) compounds polar (lipid insoluble) –so that
they are not reabsorbed in the renal tubules and are excreted.
 Most hydrophilic drugs, e.g. Streptomycin is little biotransformed and are
largely excreted unchanged.
The Phases of Drug Metabolism
• Phase 1 reactions- convert lipophilic drugs into more polar molecules by introducing a
polar functional group (-OH ,-COOH, -SH, -NH2)
• reduction, oxidation, or hydrolysis reactions;
• Phase 2 reactions- enzymes catalyze the conjugation of the substrate (the phase 1
product) with an endogenous molecule.
Pharmacokinetics
Pharmacokinetics
Pharmacokinetics
Pharmacokinetics
Pharmacokinetics
 Age: reduced numbers of hepatocytes and enzyme activity
 Diseases that reduce blood flow to liver (heart failure/shock) reduce its metabolic
activity
 Genetic Polymorphism
 Drugs and diet etc that reduce liver function
 Inhibit cytochrome P450
E.g. Grapefruit juice
 Increase P450 activity
Smoking and brussel sprouts,
St. John’s wort
Bergamottin,
a natural Furanocoumarin in
both grapefruit flesh and
peel that inhibits
the CYP3A4 enzyme.
 All the processes that may be involved in removing a parent drug from the body.
 Renal excretion and hepatic metabolism are major processes of drug elimination
 The liver is principally responsible for metabolism and the kidneys for elimination
 Glomerular filtration
 Tubular reabsorption
 Tubular secretion
Rate of Excretion= (Rate of Filtration + Rate of Secretion) –
(Rate of Reabsorption)
Net renal excretion = (GF + TS) – TR
Excretion of water soluble substances.
Elimination of drugs via the kidneys into urine
involves the processes ;-
Glomerular filtration:
• Drugs enter the kidney through renal arteries, which divide to form a
glomerular capillary plexus.
• Free drug (not bound to albumin) flows through the capillary slits into the
Bowman space as part of the glomerular filtrate .
• The glomerular filtration rate (GFR) is normally about 125 mL/min but
may diminish significantly in renal disease.
• Lipid solubility and pH do not influence the passage of drugs into the
glomerular filtrate.
• However, variations in GFR and protein binding of drugs do affect this
process.
Proximal tubular secretion:
 Drugs that were not transferred into the glomerular filtrate leave the
glomeruli through efferent arterioles, which divide to form a capillary
plexus surrounding the nephric lumen in the proximal tubule.
 Secretion primarily occurs in the proximal tubules by two energy-
requiring active transport systems: one for anions (for example,
deprotonated forms of weak acids) and one for cations (for example,
protonated forms of weak bases).
 Each of these transport systems shows low specificity and can
transport many compounds. Thus, competition between drugs for
these carriers can occur within each transport system.
 [Note: Premature infants and neonates have an incompletely
developed tubular secretory mechanism and, thus, may retain certain
drugs in the glomerular filtrate.]
Distal tubular reabsorption:
 As a drug moves toward the distal convoluted tubule, its concentration
increases and exceeds that of the perivascular space.
 The drug, if uncharged, may diffuse out of the nephric lumen, back into the
systemic circulation.
 Manipulating the urine pH to increase the fraction of ionized drug in the lumen
may be done to minimize the amount of back diffusion and increase the
clearance of an undesirable drug.
 As a general rule, weak acids can be eliminated by alkalinization of the urine,
whereas elimination of weak bases may be increased by acidification of the
urine.
 This process is called “ion trapping.”
 For example, a patient presenting with phenobarbital (weak acid) overdose
can be given bicarbonate, which alkalinizes the urine and keeps the drug
ionized, thereby decreasing its reabsorption.
 Physiochemical properties of drugs
 Molecular weight
 Lipid solubility
 Volume of distribution
 Binding character
 Degree of ionization
 Blood flow to the kidney
 Urine pH
 Biological factor e.g. age
 Disease states
 Drug MW (Molecular Weight): - Larger MW drugs are difficult to be excreted
than smaller MW especially by glomerular filtration.
 Drug lipid solubility: urinary excretion is inversely related to lipophilicity,
increased lipid solubility increase volume of distribution of drug and decrease
renal excretion.
 Volume of distribution: A drug with large Vd is poorly excreted in urine. Drugs
restricted to blood (low vd) have higher excretion rates.(The larger the volume of
distribution, the more likely that the drug is found in the tissues of the body. The
smaller the volume of distribution, the more likely that the drug is confined to the
circulatory system.)
 Renal blood flow: increased perfusion leads to increased excretion; Important for
drugs excreted by glomerular filtration.
 Drug Clearance-Clearance is the measure of removal of drug from the body.
 The conc of drug in plasma is affected by rate at which its administered, Vd and
its clearance
 A drug’s clearance and the Vd determines it’s half life
 Drug clearance is defined as the volume of blood or plasma (containing the drug)
that is completely cleared from the drug per unit of time
 Clearance does not indicate the amount of drug being removed, but the volume
of plasma/ blood from which the drug is completely removed or cleared, in a unit
time
• The units for clearance are volume/ time (eg, mL/min, L/h). For example, if the Cl
of penicillin is 15 mL/min in a patient and penicillin has a VD of 12 L, then from
the clearance definition, 15 mL of the 12 L will be removed from the drug per
minute.
• The definition of clearance is the volume of serum or blood completely
cleared of the drug per unit time.
• Thus, the dimension of clearance is volume per unit time, such as L/h or
mL/min. The liver is most often the organ responsible for drug
metabolism while in most cases the kidney is responsible for drug
elimination.
• The gastrointestinal wall, lung, and kidney can also‘‘a proportionality
constant describing the relationship between a substance’s rate of
elimination (amount per unit time) at a given time and its corresponding
concentration in an appropriate fluid at that time
• The clearance of a drug is the theoretical volume of plasma from which
the drug is completely removed in unit time.
 The rate of elimination describes the amount of drug being cleared
 Drug elimination rate is defined as 'the amount of drug cleared from the blood
per unit time'
 If the drug conc. In the blood is high , there is a greater amount of drug in the
volume that is cleared per unit time.
 If the drug conc. Is low, the same clearance will eliminate a smaller amount of
drug per unit time.
 The rate of drug elimination from the body is the product of plasma conc. and
its plasma clearance
 Rate of drug elimination is inversely proportional to Vd
Elimination rate
Clearance ;
Concentration
Clearance xElimination rate ; Concentration
mg/hr
mg/L
L/hr
mg/hr L/hr mg/L
Elimination rate (kidney)
CL(kidney) =
C
Elimination rate (liver)
CL(liver) =
C
Elimination rate (other)
CL(other) =
C
CL(systemic) = CL(kidney) + CL(liver) + CL(other)
Elimination rate α Concentration
CL; A proportionality constant that
relates a substance’s rate of
elimination from the body at a given
time and its blood/plasma/serum
concentration at that time
dD/dt
Rate of drug elimination is
inversely proportional to Vd
Elimination rate α
Volume of Distribution
1
Half life of drug
 Plasma half-life (t½) of a drug is the time taken for its plasma concentration to be
reduced to half of its original value.
 Time required for drug conc. in body or blood to decrease by 50%
 Determines the frequency of dosing required to maintain therapeutic plasma
levels of a drug
 Half-life is determined by clearance (CL) and volume of distribution (VD) and the
relationship is described by the following equation:
t1/2 = 0.693 Vd /CL
Half life is increased by an increase in the volume of distribution and increased by
a decrease in the rate of clearance.
In some disease states (eg. renal failure with oedema) volume of distribution
increases but clearance decreases, resulting in an unchanged half life (thus, it is a
poor measure of drug clearance alone).
Plasma half-life (t1/2) of some drugs
 Benzylpenicillin: 30 min
 Amoxicillin: 1 hr
 Paracetamol: 2 hr
 Atenolol: 7 hr
 Diazepam: 40 hr
t1/2 Plasma conc.
(mg)
0 100
1 50
2 25
3 12.5
4 6.25
5 3.125
Pharmacokinetics
Bioavailability, the fraction of drug absorbed as such into the systemic circulation.
Volume of distribution, a measure of the apparent space in the body available to
contain the drug based on how much is given versus what is found in the systemic
circulation.
 Volume of distribution does not represent a real volume but must be regarded as
the size of the body or fluids that would be required if the drug was distributed eqaully
in all portions of the body.
Clearance, a measure of the body’s efficiency in eliminating drug from the systemic
circulation.
 Elimination t1/2, a measure of the rate of removal of drug from the systemic
circulation.
 Medical Pharmacology and Therapeutics ; Derek G. Waller, Tony Sampson
 Pharmacology and Therapeutics for Dentistry - John A. Yagiela, Frank J.
Dowd, Elsevier Health Sciences
 Lippincott Illustrated Reviews: Pharmacology, Karen Whalen, 6th edition ,Wolters
Kluwer
 Basic Pharmacokinetics, Mohsen A. Hedaya, CRC Press
 Basic and Clinical Pharmacology, Bertram Katzung, Anthony Trevor, 13th edition,
McGraw Hill
 Essentials of Medical Pharmacology, KD Tripathi, 7th edition, JAYPEE BROTHERS
MEDICAL PUBLISHERS .
 Principles of Clinical Pharmacology, Arthur J. Atkinson, Jr., Darrell R.
Abernethy, Elsevier
 Pharmacology: Principles and Practice, Miles Hacker, William S. Messer. Academic
Press
 Goodman and Gilman's The Pharmacological Basis of Therapeutics, Laurence
Brunton, Bruce Chabner, 13
th
edition McGraw Hill
 Slideshare
References
Pharmacokinetics

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Pharmacokinetics

  • 1. Akash Mahadev Iyer S4 M Sc Biochemistry Department of biochemistry Karyavattom campus University of Kerala How does the human body act on the drugs?
  • 2.  The interactions between a drug and the body are conveniently divided into two classes.  Pharmacokinetic processes  Pharmacodynamic processes
  • 3. • Pharmaco- Greek word (pharmackon) for “drug,”, and kinetics from the Greek word (kinetikos) for “moving,”. • Pharmacokinetics (PK) is the study of drug movement into, around, and out of the body - drug absorption, distribution, and elimination (metabolism and excretion) (ADME). 1. Absorption: from the site of administration permits entry of the drug (either directly or indirectly) into plasma. 2. Distribution: the drug may then reversibly leave the bloodstream and distribute into the interstitial and intracellular fluids. 3. Metabolism: the drug may be biotransformed by metabolism by the liver or other tissues. 4. Elimination: the drug and its metabolites are eliminated from the body in urine, bile, or feces. Pharmacokinetics refers to what the body does to a drug, whereas pharmacodynamics describes what the drug does to the body.
  • 5. • Absorption is the transfer of a drug from the site of administration to the bloodstream. • The Plasma Membrane Is Selectively Permeable • Passive diffusion dominates transmembrane movement of most drugs.  Active processes play a role in the movement of many drugs, whose molecules are too large to diffuse readily. CARRIER MEDIATED
  • 6. OUT OUTIN IN Used to transport drugs of large size across the cell membrane. Endocytosis -engulfment of a drug by the cell membrane and transport into the cell by pinching off the drug filled vesicle. Uptake of extracellular material by its inclusion in a vesicle formed by invagination of the Plasma membrane Exocytosis -reverse of endocytosis, the fusion of intracellular vesicle with plasma membrane , releasing the vesicle contents to extracellular space Cells use exocytosis to secrete substances out of the cell.
  • 7. Factors influencing rate of absorption  Route of administration- influences bioavailability  IV administration- immediate and complete absorption.  Extravascularly administered - carried through various barriers to reach the blood circulation and their site of action.  Concentration of drug- Increase in conc. increases rate of absorption  pH – influences the lipid solubility  Molecular size: The smaller in size-----more absorption  Surface area - The more absorptive surface area, the more absorption.  Brush borders of the intestine -1000-fold SA to that of the stomach, - Hence EFFICIENT ABSORPTION….  Blood Flow- The intestines receive much more blood flow than the stomach, so absorption from the intestine is favored over the stomach.  Contact time at the absorption surface: If a drug moves through the GI tract very quickly (in severe diarrhea), it is not well absorbed.  Food in the stomach -dilutes the drug and slows gastric emptying.- drug taken with a meal is generally absorbed more slowly
  • 8. Expression of P-glycoprotein  P-glycoprotein is a TM transporter  Phosphorylated protein of MDR family of ABCs transporters,  Expressed in - liver, kidneys, placenta, intestines etc.  Involved in transportation of drugs from tissues to blood-“pumps” drugs out of the cells.  Thus, in areas of high expression, P-glycoprotein reduces drug absorption
  • 9. Effect of pH on drug absorption • Most drugs are weak organic acids or bases, so they undergo ionization • Ionization of drugs reduces its ability to permeate membranes- (REDUCES LIPOPHILICITY…) A drug is present in solution as both the  Lipid-soluble, diffusible, non-ionized form and  The ionized form - lipid insoluble and poorly diffusible across a membrane.  Common ionizable groups -COOH, -NH2 o (1º, 2º, 3º, and 4º amines hold a permanent +ve charge ). • The degree of ionization of a drug is determined by the surrounding pH and pKa of the drug
  • 10. A drug passes through membranes more readily if it is uncharged
  • 11.  A drug passes through membranes more readily if it is uncharged. Thus, for a weak acid, the uncharged, protonated HA can permeate through membranes, and A− cannot.  For a weak base, the uncharged form B penetrates through the cell membrane, but the protonated form BH+ does not. Therefore, the effective concentration of the permeable form of each drug at its absorption site is determined by the relative concentrations of the charged and uncharged forms. The ratio between the two forms is, in turn, determined by the pH at the site of absorption and by the strength of the weak acid or base, which is represented by the ionization constant, pKa.  [Note: The pKa is a measure of the strength of the interaction of a compound with a proton.  The lower the pKa of a drug, the more acidic it is. Conversely, the higher the pKa, the more basic is the drug.] Distribution equilibrium is achieved when the permeable form of a drug achieves an equal concentration in all body water spaces.
  • 12. pH  pH is simply a measure of the [H+] concentration in a given solution  pKa is defined as the pH were a drug exists as 50% ionized and 50% unionized. If pKa - pH = 0, then 50% of drug is ionized and 50% is unionized.  Before explaining the ionization and absorption processes of these drugs, it is important to understand the equilibrium step for the non-ionized (un-dissociated) and ionized (dissociated) forms. This equilibrium is described by the following equation, commonly known as the Henderson– Hasselbalch equation, and is written as follows:
  • 13. Ionization of Weak Acids and Weak Bases; Henderson-Hasselbalch Equation  A weak acid - neutral molecule that can reversibly dissociate into an anion and a proton (a hydrogen ion).  A weak base; neutral molecule that can reversibly dissociated into a cation and a proton HA H+ + A- Ka B + H+BH+ Kb pKa=pH+log(HA/A-) pKb=pH+log(BH+/B)
  • 14. Aspirin is reasonably absorbed from stomach pKa of Aspirin= 3.4 (50 % HA and 50% A- ) at pH 3.4) If pH < pKa – drug is unionised (High H+ in surrounding envt) -If the pH is lower than the pKa, then the compound will be protonated. If pH > pKa – drug is ionised - If the pH is higher than the pKa, then the compound will be deprotonated.
  • 16.  Bioavailability is defined as the fraction of unchanged drug reaching the systemic circulation, following administration by any route.  Expressed as percentage.  If a 1 gram dose of a drug is administered by mouth, and half of that reaches the systemic circulation, the drug is 50% bioavailable. Determination of bioavailability:  Bioavailability is determined by comparing plasma levels of a drug after a particular route of administration (for eg; oral administration) with levels achieved by IV administration. F = AUC (oral) AUC (iv) x 100
  • 17.  After IV administration, 100% of the drug rapidly enters the circulation. When the drug is given orally, only part of the administered dose appears in the plasma.  By plotting plasma concentrations of the drug versus time, the area under the curve (AUC) can be measured.  The total AUC reflects the extent of absorption of the drug. Bioavailability of a drug given orally is the ratio of the AUC following oral administration to the AUC following IV  Need for Bioavailability studies- To establish important pharmacokinetic parameters, dosage regimen, dose labelling • Also explains why the same dose may cause a therapeutic effect by one route and same dose may cause a toxic effect by another route.
  • 19. Increased risk of resistance Increased risk of side effects Missed dose/ late dose AUC; total amount of active substance which was in the bloodstream over the period studied The AUC can be derived from either single-dose studies (left) or multiple-dose measurements (right)
  • 20. MEC/ Minimum Therapeutic Dose ; Minimum conc. of drug required by the body to produce therapeutic effect MSC/ Minimum Toxic Dose ; The conc. of drug in plasma above which toxic effects are seen Therapeutic range ; The range b/w Minimum Toxic Dose and Minimum Therapeutic Dose
  • 21.  The elimination of drug that occurs after administration but before it enters the systemic circulation (eg, during passage through the gut wall, portal circulation, or liver for an orally administered drug)  Reduces amount of unchanged drug entering the systemic circulation. • All orally administered drugs are exposed to drug metabolizing enzymes in the intestinal wall and liver. This refers to metabolism of a drug during its passage from the site of absorption into the systemic circulation.
  • 22.  Route of administration  First-pass hepatic metabolism  More than 90% of nitroglycerin is cleared during first-pass metabolism. Hence, it is primarily administered via the sublingual or transdermal route. • Drugs with high first-pass metabolism should be given in doses sufficient to ensure that enough active drug reaches the desired site of action, • Drugs such as propranolol and nitrates undergo significant hepatic metabolism during a single passage through the liver  Solubility of the drug:  Very hydrophilic drugs are poorly absorbed because of their inability to cross lipid-rich cell membranes.  Drugs that are extremely lipophilic are also poorly absorbed, because they are totally insoluble in aqueous body fluids and, therefore, cannot gain access to the surface of cells.
  • 23. • When a dose of a drug is given intravenously, the whole drug reaches in circulation and the bioavailability is equal to one/ 100 %. • When a drug is administered through other route (such as orally) bioavailability maybe less than one / < 100% May be because of : • Incomplete absorption • Solubility of drug • After oral administration, a drug maybe incompletely absorbed because of too hydrophilic that cannot pass through the lipid cell membrane, or too lipophilic that the drug is not soluble enough to cross the water layer adjacent to the cell.
  • 24. Chemical instability:  Penicillin G -unstable in gastric pH.  Insulin- destroyed in the GI tract by degradative enzymes. Nature of the drug formulation:  Drug absorption may be altered by particle size, salt form, crystal polymorphism, enteric coatings, and the presence of excipients (such as binders and dispersing agents) can influence the ease of dissolution and, therefore, alter the rate of absorption
  • 25. Distribution  Drug distribution is the process by which a drug reversibly leaves the bloodstream and enters the interstitium (extracellular fluid) and the tissues.  No absorption process for IV administered drugs, is directly distributed, during which the drug rapidly leaves the circulation and enters the tissues • Passive Process, -driving force is the Conc. Gradient b/w blood and Extra- vascular Tissues. - occurs until equilibrium is established. • Distribution is not uniform throughout the body -different tissues receive the drug from plasma at different rates and to different extents. • Drug concentration in blood or plasma depends on the amount of drug present in the body as well as how extensively it is distributed. The latter can be assessed from its Vd.
  • 26. Factors affecting the rate of distribution  Blood flow; Greater Blood flow to “vessel-rich organs” (brain, liver, and kidney) than skeletal muscles.  The most vitally important organs of the body receive the greatest supply of blood. These organs include the brain, liver, and kidneys. Skeletal muscle and bone receive less blood, and adipose tissue (fat) receives the least.  Blood flow to the “vessel-rich organs” (brain, liver, and kidney) is greater than that to the skeletal muscles. • If blood flow were the only factor affecting distribution, it would be reasonable to expect that high concentrations of administered medications would always appear in the brain and liver.  Capillary permeability is determined by capillary structure and by the chemical nature of the drug.  In the liver and spleen, a significant portion of the basement membrane is exposed due to large, discontinuous capillaries through which large plasma proteins can pass  In the brain, the capillary structure is continuous  To enter the brain, drugs must pass through the endothelial cells of the CNS capillaries or be activley transported
  • 27. Bone can become a reservoir for the slow release of toxic agents such as lead or radium  To enter the brain, drugs must pass through the endothelial cells of the CNS capillaries or be actively transported.  Lipid -soluble drugs readily penetrate the CNS because they dissolve in the endothelial cell membrane. Small and highly fat-soluble anesthetic gases quickly and easily penetrate the brain to cause anesthesia,  Ionized or polar drugs generally fail to enter the CNS because they cannot pass through the endothelial cells These closely juxtaposed cells form tight junctions that constitute the blood–brain barrier.
  • 28.  Capillary permeability  Drugs molecular weight (< 500 to 600 Da) easily cross the capillary membrane to penetrate into the extracellular fluids (except in CNS) because junctions between the capillary endothelial cells are not tight  Lipophilicity  Water-soluble molecules and ions of size below 50 daltons enter the cell -aqueous filled channels,  Larger size - specialized transport system.  Different drugs binding to different proteins  Acidic drugs, Albumins Ex- Bilirubin, Bile acids, Fatty acids, Vitamin C, Salicylates, Sulfonamides, Barbiturates, Probenecid, Phenylbutazone, Penicilins, Tetracyclines etc  Basic drugs Globulins Ex- Adenosine, Quinacrine, Quinine, Streptomycin,Chloramphenicol, Digitoxin, Ouabain, Coumarin
  • 29.  Bone  The tetracycline antibiotics (and other divalent metal-ion chelating agents) and heavy metals may accumulate in bone by adsorption onto the bone crystal surface  Fat as a Reservoir  Many lipid-soluble drugs are stored in the neutral fat.  Fat - stable reservoir -it has a relatively low blood flow. When a drug enters the body, it exists in: I. Free form • Free forms are metabolized and excreted -they can cross the glomerular membrane. • Therapeutically active. II. Bound form • Not metabolized or excreted and do not have therapeutic or toxic effect. • When the free form is used up, drug is released from the reservoirs. Thus both forms exist in equilibrium. Significance: • Bound form acts as a reservoir, providing free form when required
  • 30. Volume of distribution  A direct measure of extent of distribution of a drug in rest of body compared to plasma  Vd, is defined as the fluid volume that is required to contain the entire drug in the body at the same concentration measured in the plasma.  Lipid insoluble / highly protein bound drug– restricted to vascular compartment – low Vd  Drugs sequestered in other tissues – large Vd
  • 31. The human body is not a glass beaker !!!!  Drugs distribute in and out of different tissue compartments.  The human body is (~70%) water, So, we can think of the body as containers with water:  If Vd = 7.4 L or less –drug is confined to the plasma. This may occur for two reason  The molecule is too large to leave this compartment.  The molecule binds preferably to plasma proteins (e.g. to albumin) and much less to tissue proteins.  Some drugs cannot enter cells because of their low lipid solubility. These drugs are distributed throughout the body water in the extracellular compartment and have a relatively small Vd (12-20 L).  If Vd >42 L - drug is thought to be distributed to all tissues in the body, especially the fatty tissue.  If Vd = >10,000 L! -most of the drug is in the tissues, and very little is in the plasma circulation Dose or Amount of drug in body / drug concentrationVolume of distribution =
  • 32.  Larger Vd, the more likely that the drug is found in the tissues of the body. Drugs that accumulate in organs either by active transport or by specific binding to tissue molecules.  Smaller Vd, the more likely that the drug is found in circulation • Patients with edema, ascites, or pleural effusions offer a larger volume of distribution- Due to increase in total water
  • 33. . Skeletal muscle, heart Digoxin, Emetine (bound to muscle proteins). Liver Chloroquine, Tetracyclines, Emetine, Digoxin. Kidney Digoxin, Chloroquine, Emetine. Thyroid Iodine. Brain Chlorpromazine, Acetazolamide, Isoniazid. Retina Chloroquine (bound to nucleoproteins). Iris Ephedrine, Atropine (bound to melanin). Bone and teeth Tetracyclines, Heavy Metals (bound to Mucopolysaccharides of connective tissue), Bisphosphonates (bound to Hydroxyapatite) Adipose tissue Thiopentone, Ether, Minocycline, Phenoxybenzamine, DDT dissolve in neutral fat due to high lipid-solubility; remain stored due to poor blood supply of fat.
  • 34. Drug VD Comments Warfarin 8L Reflects a high degree of plasma protein binding. Theophylline 30L Represents distribution in total body water. Chloroquine 15000L Highly lipophilic molecules which partitions into body fat NXY-059 8L Highly-charged hydrophilic molecule.
  • 35.  Once a drug enters the body, it has the potential to distribute into any one of the three functionally distinct compartments of body water or to become sequestered in a cellular site.  Plasma compartment:  Extracellular fluid  Total body water Distribution into the water compartments in the body:
  • 36. Metabolism  Biotransformation  Increases hydrophilicity Primary site of drug metabolism – liver Other sites; Kidney, intestine, lungs and plasma.  Chemical alteration of the drug in the body.  Converts non polar (lipid-soluble) compounds polar (lipid insoluble) –so that they are not reabsorbed in the renal tubules and are excreted.  Most hydrophilic drugs, e.g. Streptomycin is little biotransformed and are largely excreted unchanged. The Phases of Drug Metabolism • Phase 1 reactions- convert lipophilic drugs into more polar molecules by introducing a polar functional group (-OH ,-COOH, -SH, -NH2) • reduction, oxidation, or hydrolysis reactions; • Phase 2 reactions- enzymes catalyze the conjugation of the substrate (the phase 1 product) with an endogenous molecule.
  • 42.  Age: reduced numbers of hepatocytes and enzyme activity  Diseases that reduce blood flow to liver (heart failure/shock) reduce its metabolic activity  Genetic Polymorphism  Drugs and diet etc that reduce liver function  Inhibit cytochrome P450 E.g. Grapefruit juice  Increase P450 activity Smoking and brussel sprouts, St. John’s wort Bergamottin, a natural Furanocoumarin in both grapefruit flesh and peel that inhibits the CYP3A4 enzyme.
  • 43.  All the processes that may be involved in removing a parent drug from the body.  Renal excretion and hepatic metabolism are major processes of drug elimination  The liver is principally responsible for metabolism and the kidneys for elimination
  • 44.  Glomerular filtration  Tubular reabsorption  Tubular secretion Rate of Excretion= (Rate of Filtration + Rate of Secretion) – (Rate of Reabsorption) Net renal excretion = (GF + TS) – TR Excretion of water soluble substances. Elimination of drugs via the kidneys into urine involves the processes ;-
  • 45. Glomerular filtration: • Drugs enter the kidney through renal arteries, which divide to form a glomerular capillary plexus. • Free drug (not bound to albumin) flows through the capillary slits into the Bowman space as part of the glomerular filtrate . • The glomerular filtration rate (GFR) is normally about 125 mL/min but may diminish significantly in renal disease. • Lipid solubility and pH do not influence the passage of drugs into the glomerular filtrate. • However, variations in GFR and protein binding of drugs do affect this process.
  • 46. Proximal tubular secretion:  Drugs that were not transferred into the glomerular filtrate leave the glomeruli through efferent arterioles, which divide to form a capillary plexus surrounding the nephric lumen in the proximal tubule.  Secretion primarily occurs in the proximal tubules by two energy- requiring active transport systems: one for anions (for example, deprotonated forms of weak acids) and one for cations (for example, protonated forms of weak bases).  Each of these transport systems shows low specificity and can transport many compounds. Thus, competition between drugs for these carriers can occur within each transport system.  [Note: Premature infants and neonates have an incompletely developed tubular secretory mechanism and, thus, may retain certain drugs in the glomerular filtrate.]
  • 47. Distal tubular reabsorption:  As a drug moves toward the distal convoluted tubule, its concentration increases and exceeds that of the perivascular space.  The drug, if uncharged, may diffuse out of the nephric lumen, back into the systemic circulation.  Manipulating the urine pH to increase the fraction of ionized drug in the lumen may be done to minimize the amount of back diffusion and increase the clearance of an undesirable drug.  As a general rule, weak acids can be eliminated by alkalinization of the urine, whereas elimination of weak bases may be increased by acidification of the urine.  This process is called “ion trapping.”  For example, a patient presenting with phenobarbital (weak acid) overdose can be given bicarbonate, which alkalinizes the urine and keeps the drug ionized, thereby decreasing its reabsorption.
  • 48.  Physiochemical properties of drugs  Molecular weight  Lipid solubility  Volume of distribution  Binding character  Degree of ionization  Blood flow to the kidney  Urine pH  Biological factor e.g. age  Disease states
  • 49.  Drug MW (Molecular Weight): - Larger MW drugs are difficult to be excreted than smaller MW especially by glomerular filtration.  Drug lipid solubility: urinary excretion is inversely related to lipophilicity, increased lipid solubility increase volume of distribution of drug and decrease renal excretion.  Volume of distribution: A drug with large Vd is poorly excreted in urine. Drugs restricted to blood (low vd) have higher excretion rates.(The larger the volume of distribution, the more likely that the drug is found in the tissues of the body. The smaller the volume of distribution, the more likely that the drug is confined to the circulatory system.)  Renal blood flow: increased perfusion leads to increased excretion; Important for drugs excreted by glomerular filtration.
  • 50.  Drug Clearance-Clearance is the measure of removal of drug from the body.  The conc of drug in plasma is affected by rate at which its administered, Vd and its clearance  A drug’s clearance and the Vd determines it’s half life  Drug clearance is defined as the volume of blood or plasma (containing the drug) that is completely cleared from the drug per unit of time  Clearance does not indicate the amount of drug being removed, but the volume of plasma/ blood from which the drug is completely removed or cleared, in a unit time • The units for clearance are volume/ time (eg, mL/min, L/h). For example, if the Cl of penicillin is 15 mL/min in a patient and penicillin has a VD of 12 L, then from the clearance definition, 15 mL of the 12 L will be removed from the drug per minute.
  • 51. • The definition of clearance is the volume of serum or blood completely cleared of the drug per unit time. • Thus, the dimension of clearance is volume per unit time, such as L/h or mL/min. The liver is most often the organ responsible for drug metabolism while in most cases the kidney is responsible for drug elimination. • The gastrointestinal wall, lung, and kidney can also‘‘a proportionality constant describing the relationship between a substance’s rate of elimination (amount per unit time) at a given time and its corresponding concentration in an appropriate fluid at that time • The clearance of a drug is the theoretical volume of plasma from which the drug is completely removed in unit time.
  • 52.  The rate of elimination describes the amount of drug being cleared  Drug elimination rate is defined as 'the amount of drug cleared from the blood per unit time'  If the drug conc. In the blood is high , there is a greater amount of drug in the volume that is cleared per unit time.  If the drug conc. Is low, the same clearance will eliminate a smaller amount of drug per unit time.  The rate of drug elimination from the body is the product of plasma conc. and its plasma clearance  Rate of drug elimination is inversely proportional to Vd
  • 53. Elimination rate Clearance ; Concentration Clearance xElimination rate ; Concentration mg/hr mg/L L/hr mg/hr L/hr mg/L Elimination rate (kidney) CL(kidney) = C Elimination rate (liver) CL(liver) = C Elimination rate (other) CL(other) = C CL(systemic) = CL(kidney) + CL(liver) + CL(other) Elimination rate α Concentration CL; A proportionality constant that relates a substance’s rate of elimination from the body at a given time and its blood/plasma/serum concentration at that time dD/dt Rate of drug elimination is inversely proportional to Vd Elimination rate α Volume of Distribution 1
  • 54. Half life of drug  Plasma half-life (t½) of a drug is the time taken for its plasma concentration to be reduced to half of its original value.  Time required for drug conc. in body or blood to decrease by 50%  Determines the frequency of dosing required to maintain therapeutic plasma levels of a drug  Half-life is determined by clearance (CL) and volume of distribution (VD) and the relationship is described by the following equation: t1/2 = 0.693 Vd /CL Half life is increased by an increase in the volume of distribution and increased by a decrease in the rate of clearance. In some disease states (eg. renal failure with oedema) volume of distribution increases but clearance decreases, resulting in an unchanged half life (thus, it is a poor measure of drug clearance alone).
  • 55. Plasma half-life (t1/2) of some drugs  Benzylpenicillin: 30 min  Amoxicillin: 1 hr  Paracetamol: 2 hr  Atenolol: 7 hr  Diazepam: 40 hr t1/2 Plasma conc. (mg) 0 100 1 50 2 25 3 12.5 4 6.25 5 3.125
  • 57. Bioavailability, the fraction of drug absorbed as such into the systemic circulation. Volume of distribution, a measure of the apparent space in the body available to contain the drug based on how much is given versus what is found in the systemic circulation.  Volume of distribution does not represent a real volume but must be regarded as the size of the body or fluids that would be required if the drug was distributed eqaully in all portions of the body. Clearance, a measure of the body’s efficiency in eliminating drug from the systemic circulation.  Elimination t1/2, a measure of the rate of removal of drug from the systemic circulation.
  • 58.  Medical Pharmacology and Therapeutics ; Derek G. Waller, Tony Sampson  Pharmacology and Therapeutics for Dentistry - John A. Yagiela, Frank J. Dowd, Elsevier Health Sciences  Lippincott Illustrated Reviews: Pharmacology, Karen Whalen, 6th edition ,Wolters Kluwer  Basic Pharmacokinetics, Mohsen A. Hedaya, CRC Press  Basic and Clinical Pharmacology, Bertram Katzung, Anthony Trevor, 13th edition, McGraw Hill  Essentials of Medical Pharmacology, KD Tripathi, 7th edition, JAYPEE BROTHERS MEDICAL PUBLISHERS .  Principles of Clinical Pharmacology, Arthur J. Atkinson, Jr., Darrell R. Abernethy, Elsevier  Pharmacology: Principles and Practice, Miles Hacker, William S. Messer. Academic Press  Goodman and Gilman's The Pharmacological Basis of Therapeutics, Laurence Brunton, Bruce Chabner, 13 th edition McGraw Hill  Slideshare References

Hinweis der Redaktion

  1. Pharmacokinetics refers to what the body does to a drug, whereas pharmacodynamics describes what the drug does to the body.
  2. acid is that it is a substance, charged or uncharged, that liberates hydrogen ions (H+) in solution. A base is a substance that can bind H+ and remove them from solution. Strong acids, strong bases, as well as strong electrolytes are essentially completely ionized in aqueous solution. Weak acids and weak bases are only partially ionized in aqueous solution and yield a mixture of the undissociated compound and ions.
  3. After IV administration, 100% of the drug rapidly enters the circulation. When the drug is given orally, only part of the administered dose appears in the plasma. By plotting plasma concentrations of the drug versus time, the area under the curve (AUC) can be measured. The total AUC reflects the extent of absorption of the drug. Bioavailability of a drug given orally is the ratio of the AUC following oral administration to the AUC following IV Need for Bioavailability studies- To establish important pharmacokintic parameters, dosage regimen, dose labelling Also explains why the same dose may cause a therapeutic effect by one route and same dose may cause a toxic effect by another route.
  4. The time where the highest concentration of the active substance is found in the blood is called Tmax, and the maximum concentration of the active substance found in the blood stream is called Cmax. After a tablet or capsule is swallowed, it reaches the stomach within a minute or two.1 In the stomach, the tablet or capsule is dissolved, and some of the active substance is absorbed into the bloodstream. The components are transported to the small intestine where absorption is completed. Absorption from the gastrointestinal system can vary greatly. Lower bioavailability can be the result of poor or no absorption from the stomach and the intestines, so this step is an important one that can influence availability. When the active substance is absorbed, it reaches the hepatic portal vein first, and is transported to the liver. This is the first time the active substance is metabolised in the liver, referred to as the ‘first pass metabolism’. Some active substances are metabolised to a larger extent than others during this first time metabolism. The non-metabolised part of the active substance, normally less than 100%, will reach systematic circulation via the hepatic vein. The amount that actually reaches systemic circulation is referred to as the ‘absolute bioavailability’. Absolute bioavailability compares the bioavailability of the API in systemic circulation following non-intravenous administration with the bioavailability of the same medicine following intravenous administration. It is the percentage of the API absorbed through non-intravenous administration compared with the corresponding same medicine administered intravenously. Briefly, in absolute bioavailability the standard is always IV. Relative bioavailability measures the bioavailability of a formulation (A) of a certain medicine when compared with another formulation (B) of the same medicine, usually an established standard other than IV, or through administration via a different route. Bioavailability is affected by a number of other factors, which are particular to any one individual. See the attached fact sheet for some examples of bioavailability
  5. This refers to metabolism of a drug during its passage from the site of absorption into the systemic circulation.
  6. When a dose of a drug is given intravenously, the whole drug reaches in circulation and the bioavailability is equal to one/ 100 %. When a drug is administered through other route (such as orally) bioavailability maybe less than one / < 100% May be because of : Incomplete absorption Solubility of drug After oral administration, a drug maybe incompletely absorbed because of too hydrophilic that cannot pass through the lipid cell membrane, or too lipophilic that the drug is not soluble enough to cross the water layer adjacent to the cell.
  7. The elimination of drug that occurs after administration but before it enters the systemic circulation (eg, during passage through the gut wall, portal circulation, or liver for an orally administered drug)-First pass effect Some drugs, such as penicillin G, are unstable in the pH of the gastric contents. Others, such as insulin, are destroyed in the GI tract by degradative enzymes. Nature of the drug formulation: Drug absorption may be altered by particle size, salt form, crystal polymorphism, enteric coatings, and the presence of excipients (such as binders and dispersing agents) can influence the ease of dissolution and, therefore, alter the rate of absorption
  8. The distribution of a drug from the plasma to the interstitium depends on cardiac output and local blood flow, capillary permeability, the tissue volume, the degree of binding of the drug to plasma and tissue proteins, and the relative lipophilicity of the drug. Movement of drug proceeds until an equilibrium is established between unbound drug in the plasma and the tissue fluids. Apparent volume of distribution (V) Presuming that the body behaves as a single homogeneous compartment with volume V into which the drug gets immediately and uniformly distributed As the pharmacological action of a drug depends upon its concentration at the site of action distribution plays a significant role in the onset, intensity, and duration of action.
  9. The most vitally important organs of the body receive the greatest supply of blood. These organs include the brain, liver, and kidneys. Skeletal muscle and bone receive less blood, and adipose tissue (fat) receives the least. Blood flow to the “vessel-rich organs” (brain, liver, and kidney) is greater than that to the skeletal muscles. If blood flow were the only factor affecting distribution, it would be reasonable to expect that high concentrations of administered medications would always appear in the brain and liver. Capillary permeability is determined by capillary structure and by the chemical nature of the drug. In the liver and spleen, a significant portion of the basement membrane is exposed due to large, discontinuous capillaries through which large plasma proteins can pass In the brain, the capillary structure is continuous To enter the brain, drugs must pass through the endothelial cells of the CNS capillaries or be actively transported.. Bone can become a reservoir for the slow release of toxic agents such as lead or radium To enter the brain, drugs must pass through the endothelial cells of the CNS capillaries or be actively transported. Lipid -soluble drugs readily penetrate the CNS because they dissolve in the endothelial cell membrane. Small and highly fat-soluble anesthetic gases quickly and easily penetrate the brain to cause anesthesia, Ionized or polar drugs generally fail to enter the CNS because they cannot pass through the endothelial cells These closely juxtaposed cells form tight junctions that constitute the blood–brain barrier.
  10. In obese persons, the fat content of the body may be as high as 50%, and even in lean individuals, fat constitutes 10% of body weight;
  11. Apparent - seeming real or true, but not necessarily so. A drug's volume of distribution is that volume of bodily fluid into which a drug dose is dissolvedIt is defined as the volume in which the amount of drug would be uniformly distributed to produce the observed blood concentration. Apparent volume necessary to contain amount of drug homogenously at the same conc. found in plasma • The apparent or hypothetical volume in the body into which a drug distributes. “the volume that would accommodate all the drug in the body, if the concentration throughout was the same as in plasma”. The Volume of distribution (VD), also known as Apparent volume (all parts of the body equilibrated with the drug do not have equal concentration.) of distribution, is used to quantify the distribution of a drug between plasma and the rest of the body after oral or parenteral dosing.
  12. Accordingly, a drug that accumulates in tissues as e.g. fat tissue, will have a relatively low plasma concentration with regard to the administered dose, and consequently, the calculated Vd will be high. Vd is a measure of the relative affinity of the compound for plasma / blood constituents and tissue constituents Moderately lipophilic compounds and acids have high affinity for albumin and a low Vd Competition for plasma protein binding sites can occur between such drugs or with endogenous substances. Therefore, if we know the dose that was given, and we can measure the serum level (concentration), then we can calculate a volume:
  13. Plasma compartment: If a drug has high molecular weight or is extensively protein bound, it is too large to pass through the junctions of the capillaries and, thus, is effectively trapped within the plasma (vascular) compartment. Extracellular fluid: If a drug has a low molecular weight but is hydrophilic, it can pass through the endothelial slit junctions of the capillaries into the interstitial fluid. Hydrophilic drugs cannot move across the lipid membranes of cells to enter the intracellular fluid. Total body water: If a drug has a low molecular weight and is lipophilic, it can move into the interstitium through the slit junctions and also pass through the cell membranes into the intracellular fluid. These drugs distribute into a volume of about 60% of body weight or about 42 L in a 70-kg individual. Ethanol exhibits this apparent
  14. hase II: This phase consists of conjugation reactions. If the metabolite from phase I metabolism is sufficiently polar, it can be excreted by the kidneys. However, many phase I metabolites are still too lipophilic to be excreted. A subsequent conjugation reaction with an endogenous substrate, such as glucuronic acid, sulfuric acid, acetic acid, or an amino acid, results in polar, usually more water-soluble compounds that are often therapeutically inactive. A notable exception is morphine-6-glucuronide, which is more potent than morphine. Glucuronidation is the most common and the most important conjugation reaction. [Note: Drugs already possessing an –OH, –NH2, or –COOH group may enter phase II directly and become conjugated without prior phase I metabolism.] The highly polar drug conjugates are then excreted by the kidney or in bile. Biotransformation of drugs may lead to the following. Inactivation Most drugs and their active metabolites are rendered inactive or less active, e.g. ibuprofen, paracetamol, lidocaine, chloramphenicol, propranolol Active metabolite from an active drug- Many drugs have been found to be partially converted to one or more active metabolite; the effects observed are the sum total of that due to the parent drug and its active metabolites Activation of inactive drug Few drugs are inactive as such and need conversion in the body to one or more active metabolites. Such a drug is called a prodrug The prodrug may be more stable, having better bioavailability or other desirable pharmacokinetic properties or less side effects and toxicity.
  15.  INTERNAL FACTORS • Age Neonates have low microsomal enzymes. Eg: Chloramphenicol causing Grey baby syndrome Elderly have reduced hepatic flow • Race Chinese have high alcohol dehydrogenase, low Ald dehydrogenase • Genetic variation Slow and fast acetylators of INH (Autosomal Recessive) Atypical pseudocholinesterase for SCh (Autosomal Recessive) 35. DETERMINANTS OF DRUG METABOLISM (2/2) EXTERNAL FACTORS • Environment - Disease Liver diseases, Cardiac diseases ( blood flow to liver) & Hypothyroidism ( metabolism) • Nutrition and Diet High proteins and poor carbohydrates – enhances metabolism Starvation – inhibits microsomal enzymes • Drug-drug interaction (by stimulating/inhibiting SER development) Enzyme inducers – rifampicin, anticonvulsants Enzyme inhibitors – Valproate, cimetidine, erythromycin
  16. However, the total amount of drug reaching the infant through breast feeding is generally small and majority of drugs can be given to lactating mothers without ill effects on the infant. Nevertheless, it is advisable to administer any drug to a lactating woman only when essential. Drugs that are safe, as well as those contraindicated during breast feeding organic acids (especially drug glucuronides by OATP and MRP2), organic bases (by OCT), other lipophilic drugs (by P-gp) and steroids by distinct nonspecific active transport mechanisms. larger molecules (MW > 300) -eliminated in the bile. Urine - excretion for majority of drugs. Faeces - unabsorbed fraction and Biliary excretion. Liver actively transports drugs into bile- Enterohepatic cycling -longer stay of the drug in the body. Drugs that attain high concentrations in bile erythromycin, ampicillin, rifampin, tetracycline, oral contraceptives. Certain drugs are excreted directly in colon, e.g. anthracene purgatives, heavy metals. Exhaled air Gases and volatile liquids (general anaesthetics, alcohol) are eliminated by lungs. Saliva and sweat - Li, KI ,rifampin and heavy metals - present in significant amounts. Milk- Drugs enter breast milk by passive diffusion. Milk has a lower pH (7.0) than plasma, basic drugs are more concentrated in it.
  17. 4. Role of drug metabolism: Most drugs are lipid soluble and, without chemical modification, would diffuse out of the tubular lumen when the drug concentration in the filtrate becomes greater than that in the perivascular space. To minimize this reabsorption, drugs are modified primarily in the liver into more polar substances via phase I and phase II reactions (described above). The polar or ionized conjugates are unable to back diffuse out of the kidney lumen Glomerular capillaries have pores larger than usual; all nonprotein bound drug (whether lipid-soluble or insoluble) presented to the glomerulus is filtered. Thus, glomerular filtration of a drug depends on its plasma protein binding and renal blood flow. Glomerular filtration rate (g.f.r.), normally ~ 120 ml/min, declines progressively after the age of 50, and is low in renal failure. lomerular Filtration and Urine Formation A normal adult male subject has a GFR of approximately 125 mL/min.About 180 L of fluid per day are filtered through the kidneys.In spite of this large filtration volume, the average urine volume is 1–1.5 L.Up to 99% of the fluid volume filtered at the glomerulus is reabsorbed. Besides fluid regulation, the kidney also regulates the retention or excretion of various solutes and electrolytes.With the exception of proteins and protein-bound substances, most small molecules are filtered through the glomerulus from the plasma. 15 Renal Excretion of drugs The most important organ for drug excretion is the kidney.The principal processes that determine theurinary excretion of drugs are:Glomerular filtration.Active tubular secretion.Passive or active tubular re-absorption. 16 Glomerular filtration (GF) Driving force for GF is hydrostatic pressure of blood flowing in capillaries.Hydrostatic pressure pushes a portion of blood to be filtered across a semi-permeable membrane into the Bowman’s Capsule.Most drugs are filtered through glomerulus.Blood cells, platelets, and plasma proteins are retained in the blood and not filtered.16  17 Active Tubular Secretion of drugs occurs mainly in proximal tubulesIt increases drug concentration in filtrateDrugs undergo active secretion have excretion rate values greater than normal GFRSecretion of K+, H+, ammonia; excess amino acidsSecretion of ionized drugs into the lumene.g. penicillin 18 Characters of active tubular secretion: Is an active processneeds energyrequires carriers (transporters)can transport drugs against concentration gradientsSaturableNot specific (competition may happens)18  19 System for secretion of organic acids/anions Two secretion mechanisms are identifiedSystem for secretion of organic acids/anionsPenicillin, salicylates, sulfonamidesProbenecid, uric acidSystem for organic bases / cationsAtropine, morphineCatecholamines, quinine, neostigmine 20 Tubular re-absorption After glomerular filtration, drugs may be reabsorbed from tubular lumen into systemic circulation.It takes place all along the renal tubules.Drugs undergo tubular re-absorption have excretion rates less than the GFR. e.g. GlucoseRe-absorption increases half life of a drug.Re-absorption may be active or passive.20  21 Active tubular re-absorption It occurs with endogenous substances or nutrients that the body needs to conserve. e.g. glucose, electrolytes, amino acids, uric acid, vitamins.Probenecid acts as a uricosuric agent in treatment of gout.It increases excretion of uric acid in urine by inhibiting active tubular re-absorption of the endogenous metabolite uric acid.21  22 Passive Tubular re-absorption and urinary pH trapping (Ion trapping) Most drugs are weak acids or weak bases thus by changing pH of urine via chemicals can inhibit the passive tubular re-absorption of drugs.Urine is normally slightly acidic and favors excretion of basic drugs. 23 Renal Drug Excretion  24 Renal Drug ExcretionFor acidic drugs with pKa values from 3 to 8, a change in urinary pH affects the extent of dissociation.The extent of dissociation is more greatly affected by changes in urinary pH for drugs with a pKa of 5 than with a pKa of 3.Weak acids with pKa values of less than 2 are highly ionized at all urinary pH values and are only slightly affected by pH variations.For a weak base drug, the Henderson–Hasselbalch equation is given as 25 Renal Drug Excretion  26 Renal Drug ExcretionThe greatest effect of urinary pH on reabsorption occurs with weak base drugs with pKa values of 7.5–10.5.From the Henderson–Hesselbalch relationship, a concentration ratio for the distribution of a weak acid or basic drug between urine and plasma may be derived.The urine–plasma (U/P) ratios for these drugs are as follows. 27 Renal Drug Excretion  28 Renal Drug ExcretionFor example, amphetamine, a weak base, will be reabsorbed if the urine pH is made alkaline and more lipid-soluble nonionized species are formed.In contrast, acidification of the urine will cause the amphetamine to become more ionized (form a salt).The salt form is more water soluble and less likely to be reabsorbed and has a tendency to be excreted into the urine more quickly.In the case of weak acids (such as salicylic acid), acidification of the urine causes greater reabsorption of the drug and alkalinization of the urine causes more rapid excretion of the drug. 29 Factors affecting renal excretion of drug Physiochemical properties of drugsMolecular weightLipid solubilityVolume of distributionBinding characterDegree of ionizationBlood flow to the kidneyUrine pHBiological factor e.g. ageDisease states Renal Excretion : Renal Excretion Glomerular filtration Tubular secretion Tubular Glomerular filtration:: Glomerular filtration: Non-selective Unidirectional Ionized or unionized are filtered Plasma protein binding – decrease renal excretion Driving force - hydrostatic pressure of the blood flowing in the capillaries . Renal blood flow – increase excretion Active tubular secretion:: Active tubular secretion: Most efficient In proximal tubule of nephron . Carrier mediated-capacity limited- Saturable . Requires energy Bidirectional Unaffected by pH & protein binding. Dependent on renal blood flow. Active tubular secretion:: Active tubular secretion: OAT- secretion of organic acids/anions: e.g. penicillin, probenecid,salicylates , indomethacin , nitofurantoin,methotrexate & endogenous substances like Uric acid. OCT-organic bases or cations : e.g.Thiazide,Amiloride,Furosemide,Procainamide,Quinine,Cimetidine Active tubular secretion: Active tubular secretion Competition Similar structure Similar ionic charge Same carrier A drug with greater rate of clearance will retard the excretion of other drug with which it competes 12 Therapeutic advantages : Therapeutic advantages Probenecid acts as a uricosuric agent in treatment of gout Competitively inhibits OATP. Suppresses reabsorption of endogenous metabolite uric acid. Probenicid inhibits active tubular secretion of organic acids e.g. Penicillin- increases their plasma conc. 2 fold. 13 PowerPoint Presentation: OATP Uric acid Penicillin Probenecid X X Uricosuric Increase plasma conc PowerPoint Presentation: OATP Uric acid Nitrofurantoin Probenecid X X Decrease urinary conc Therapeutic disadvantages Other competitions: Other competitions Salicylates block uricosuric action of probenecid Probenecid and Salicylates impair tubular secretion of methotrexate Sulfinpyrazne inhibit excretion of tolbutamide Tubular Reabsorption: Tubular Reabsorption Passive diffusion All along renal tubule. Increases half-life of a drug. Lipid solubility: Lipid soluble- 99% reabsorbed Ionisation : - Ionised drugs can’t undergo reabsorption - Acidic drugs excreted in alkaline urine - Basic drugs excreted in acidic urine PowerPoint Presentation: pH of urine: 4.5-7.5 pKa - 5-8 18
  18. The definition of clearance is the volume of serum or blood completely cleared of the drug per unit time. Thus, the dimension of clearance is volume per unit time, such as L/h or mL/min. The liver is most often the organ responsible for drug metabolism while in most cases the kidney is responsible for drug elimination. The gastrointestinal wall, lung, and kidney can also‘‘a proportionality constant describing the relationship between a substance’s rate of elimination (amount per unit time) at a given time and its corresponding concentration in an appropriate fluid at that time The clearance of a drug is the theoretical volume of plasma from which the drug is completely removed in unit time.