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Pharmacokinetics
What is pharmacokinetics?
• Pharmacokinetics is the study of drug movement in, through
and out of the body (ADME).
• All pharmacokinetic processes
involve transport of the drug
across biological membranes.
Biological membrane
• This is a bilayer of phospholipid molecules, the polar groups of these are oriented at
the two surfaces and the nonpolar chains are embedded in the matrix to form a
continuous sheet.
• Extrinsic and intrinsic protein molecules are adsorbed on the lipid bilayer. Some of
the intrinsic ones, which extend through the full thickness of the membrane,
surround fine aqueous pores.
Membrane Transport
• Drugs are transported across the membranes by:
- Passive diffusion
- Filtration
- Carrier transport:
-a) Facilitated diffusion
-b) Active transport
- Pinocytosis
Passive diffusion
• The drug diffuses across the membrane in the direction of its
concentration gradient
• The membrane playing no active role in the process.
• This is the most important mechanism for majority of drugs.
• Lipid-soluble drugs diffuse by dissolving in the lipoidal matrix
of the membrane.
• The greater the difference in the concentration of the drug on
the two sides of the membrane, the faster is its diffusion.
Passive diffusion
Influence of pH
• Most drugs are weak electrolytes, i.e. their ionization is pH
dependent.
• Weak acids or bases exist in both unionised and ionised form.
• Lipid-soluble non-electrolytes readily cross biological
membranes and their transport is pH independent.
• For a weak base, the ionisation reaction is:

BH  B  H
• For a weak acid:
HA  H
acidic pH


A
alkaline pH

• The ionization of a weak electrolyte is given by the HendersonHasselbalch equation:
[non-protonated electrolyte]
pH = pKa + lg -------------------------------------[protonated electrolyte]
• pKa is the dissociation constant of the weak electrolyte and is
numerically equal to the pH at which the drug is 50% ionized
• Henderson-Hasselbalch equation for weak acid:

[A ]
lg
 pH  pK а
[ HA]
• Henderson-Hasselbalch equation for weak base:
[ B]
lg

pH

pK
a

[ BH ]
• Weakly acidic drugs, which form salts
with cations, are ionized at alkaline pH.
• Weakly basic drugs, which form salts with
anions, conversely are ionized more at
acidic pH.
• Ions are lipid insoluble and do not diffuse
across a membrane
NB!
• Weakly acidic drugs could be absorbed only at acidic
pH.
• Weakly basic drugs could be absorbed only at alkaline
pH.
• Acidic drugs are ionized more in alkaline urine—do not back
diffuse in the kidney tubules and are excreted faster.
• Accordingly, basic drugs are excreted faster if urine is acidified.
Filtration
• Filtration is a passage of drugs through aqueous pores in the
membrane or through paracellular spaces.
• Lipid-insoluble drugs cross biological membranes by filtration if
their molecular size is smaller than the diameter of the pores.
• However, capillaries (except those in brain) have large
paracellular spaces and most drugs (even albumin) can filter
through these.
Carrier transport
• All cell membranes have transmembrane
proteins which serve as carriers or
transporters for drugs across the
membrane.
1)Transporters combine transiently with
substrate
2)carry the substrate to the other side of the
membrane
3) the substrate dissociates
4)the transporter returns back to its original
state.
Carrier transport
•
-
Carrier transport is:
specific for the substrate,
saturable,
competitively inhibited by analogues which utilize the same
transporter,
- much slower than the flux through channels.
Carrier transport
• Depending on requirement of energy, carrier transport is of
two types:
• Facilitated diffusion
• Active transport
Facilitated diffusion
• The transporter, solute carrier transporters (SLC), operates
passively without needing energy and translocates the
substrate in the direction of its electrochemical gradient, i.e.
from higher to lower concentration.
Active transport
• It requires energy,
• is inhibited by metabolic poisons,
• transports the solute against its
electrochemical gradient (low to high)
• resulting in selective accumulation of
the substance on one side of the
membrane.
Pinocytosis
• It is the process of transport across the cell in particulate form
by formation of vesicles.
• This is applicable to proteins
and other big molecules.
ABSORPTION
• Absorption is movement of the drug from its site of administration into
the circulation.
• Factors affecting absorption are:
-Aqueous solubility ( a drug given as watery solution is absorbed faster
than when the same is given in solid form or as oily solution).
-Concentration (a drug given as concentrated solution is absorbed faster
than from dilute solution).
-Area of absorbing surface ( The larger is the surface area, the faster is the
absorption).
-Vascularity of the absorbing surface.
-Route of administration
ROUTES OF DRUG ADMINISTRATION
LOCAL ROUTES
• 1. Topical (skin, cornea, mucous membranes)
• 2. Deeper tissues ( intra-articular injection, infiltration around a nerve (lidocaine))
SYSTEMIC ROUTES
• 1. Oral
• 2. Sublingual (s.l.) or buccal
• 3. Rectal
• 4. Cutaneous - Transdermal therapeutic systems (TTS)
• 5. Inhalation
• 6. Nasal
• 7. Subcutaneous (s.c.)
• 8. Intramuscular (i.m.)
• 9. Intravenous (i.v.)
• 10. Intradermal injection
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There are some fundamental pharmacokinetic parameters, which must
be understood:
bioavailability (F),
volume of distribution (Vd)
clearance (CL)
Plasma half-life (t½)
Steady state plasma concentration (Css)
BIOAVAILABILITY
• Bioavailability refers to the rate and extent of absorption of a drug from
a dosage form as determined by its concentration-time curve in blood.
• It is a measure of the fraction (F ) of administered dose of a drug that
reaches the systemic circulation in the unchanged form.
• Bioavailability of drug injected i.v. is 100%.
• It is frequently lower after oral ingestion because of:
- the drug may be incompletely absorbed.
- the absorbed drug may undergo first pass metabolism in the intestinal
wall/liver or be excreted in bile.
BIOAVAILABILITY
AUC oral administration
F = ------------------------------- X 100%
AUC iv administration
Absolute bioavailability - bioavailability
of some delivery methods is compared
with that of intravenous injection
Relative bioavailability - bioavailability
of some delivery methods is compared
with other delivery methods in a particular
study
Bioequivalence
• Oral formulations of a drug from different manufacturers or
different batches from the same manufacturer may have the
same amount of the drug (chemically equivalent) but may not
yield the same blood levels—biologically inequivalent.
• Two preparations of a drug are considered bioequivalent when
the rate and extent of bioavailability of the active drug from
them is not significantly different under suitable test.
DISTRIBUTION
• Once a drug has gained access to the blood stream, it gets distributed
to other tissues that initially had no drug, concentration gradient
being in the direction of plasma to tissues.
The extent and pattern of distribution of a drug depends on its:
• lipid solubility
• ionization at physiological pH (a function of its pKa)
• extent of binding to plasma and tissue proteins
• presence of tissue-specific transporters
• differences in regional blood flow.
Apparent volume of distribution
• Apparent volume of distribution (Vd) Presuming that the body behaves
as a single homogeneous compartment with volume V into which the
drug gets immediately and uniformly distributed.
• The hypothetical volume that could contain total amout of a drug in
the body at the same concentration as that present in plasma
dose administered
• Vd =—————————
plasma concentration
• Vd< VH2O (volume of body water) - drug is distributed into plasma and
extracellular fluid;
• Vd= VH2O- drug is distributed into plasma, extracellular and intracellular
fluid.
• Vd> VH2O –Drug is present in extravascular tissue (sequestration /
accumulation in tissues).
- Plasma concentration is low.
- In case of poisoning, drugs are not removed by haemodialysis
• The capillary endothelial cells in brain have tight junctions and lack large
paracellular spaces. Further, an investment of neural tissue covers the
capillaries. Together they constitute the so called blood-brain barrier
(BBB). A similar blood-CSF barrier is located in the choroid Plexus.
• Only lipid-soluble drugs are able to penetrate and have action on the
central nervous system.
• Inflammation of meninges or brain
increases the risk that some drugs
accumulate in the brain.
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Blood-brain barrier
Blood-CSF barrier
Blood-placental barrier
Blood-ocular barrier
Blood-retinal barrier
Blood–testis barrier
• Drugs may accumulate in specific organs by active transport or get
bound to specific tissue constituents.
• Drugs sequestrated in various tissues are unequally distributed, tend to
have larger Vd and longer duration of action.
• Local / general toxicity due to high
concentration.
• Chemical alteration of the drug in the body.
• It is needed to render nonpolar (lipid-soluble) compounds polar (lipidinsoluble) so that they are not reabsorbed in the renal tubules and are
excreted.
• The primary site for drug metabolism is liver; others are—kidney,
intestine, lungs and plasma.
Biotransformation of drugs may lead to the following:
• Inactivation Most drugs are rendered inactive or less active,
• Active metabolite Many drugs could be converted to one or more active
metabolite;
• Activation of inactive drug Few drugs are inactive as such and need
conversion in the body to active metabolites. Such a drug is called a
prodrug.
• The prodrug is more stable, has better bioavailability or less side effects
and toxicity.
• Biotransformation reactions can be classified into:
• Phase 1/Nonsynthetic reactions:-Oxidation
-Reduction
-Hydrolysis
• Phase 2/Synthetic reactions/Conjugation reactions/ : endogenous
radical is conjugated to the drug to form a polar highly ionized
substanse, which is easily excreted in urine or bile.
• Inhibition of drug metabolism can precipitate toxicity of the object drug
(whose metabolism has been inhibited)
• Consequences of induction:
1. Decreased intensity and/or duration of action of drugs
2. Tolerance—if the drug induces its own metabolism (autoinduction), e.g.
carbamazepine, rifampin.
• Metabolism of a drug during its passage from the site of absorption
into the systemic circulation.
• All orally administered drugs are exposed to drug metabolizing enzymes
in the intestinal wall and liver (where they first reach through the portal
vein).
• Presystemic metabolism in the gut (intestine) and liver can be
limited/avoided by administering the drug through parenteral routes.
• The first pass metabolism is an important determinant of oral
bioavailability.
• Excretion is the passage out of systemically absorbed drug.
• Drugs and their metabolites are excreted in:
1.Urine
2.Faeces
3. Exhaled air
4. Saliva and sweat
5. Milk
• The kidney is responsible for excreting all water soluble substances.
• Renal excretion = (Glomerular filtration + tubular secretion) – tubular
reabsorption
• Glomerular capillaries have pores larger than usual; all nonprotein
bound drug (whether lipid-soluble or insoluble) presented to the
glomerulus is filtered.
• Glomerular filtration of a drug
depends on its plasma protein binding
and renal blood flow.
• It is a passive diffusion and depends on lipid solubility and ionization
of the drug at the existing urinary pH.
• Lipid-soluble drugs filtered back in the tubules,
• Nonlipid-soluble and highly ionized drugs are unable to do so.
• Weak bases ionize more and are less reabsorbed in acidic urine.
• Weak acids ionize more and are less reabsorbed in alkaline urine.
• This is the active transfer of organic acids and bases by specific
transporters in the proximal tubules.
• Active transport of the drug across
tubules reduces concentration of it
in vessels.
• Drug elimination is the sumtotal of metabolic inactivation
(biotransformation) and excretion.
• Clearance (CL) – the volume of plasma which is cleared of a drug per
unit time (drug is completely removed).
• CLtotal= CLrenal + CLliver + CLlung + CLother
• It can be calculated as:
Rate of elimination
CL = -------------------------C
where C is the plasma concentration.
• The Plasma half-life (t½) of a drug is the time taken for its plasma
concentration to be reduced to half of its original value.
• Mathematically, elimination t½ is
ln2
• t½ = ------ , where - k is the elimination rate constant of the drug,
k
- ln2 - natural logarithm of 2 (or 0.693)
• k = CL / Vd
t1 2
ln 2 ln 2  Vd


k el
Cl
Nearly complete drug elimination occurs in 4–5 half lives.
• 1 t½ – 50% drug is eliminated.
• 2 t½ – 75% drug is eliminated.
• 3 t½ – 87.5% drug is eliminated.
• 4 t½ – 93.75% drug is eliminated.
• Steady state plasma concentration (Css) - the concentration of a drug in
plasma at the time a “steady state” has been achieved (rates of drug
administration and drug elimination are equal).
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dose rate
• Css = —————
•
CL
• Doubling the dose would double
the average Css.
• Doubling the dosage interval would reduce
twice the average Css.
скор _ введ D / время D / T
Css 


Cl
Cl
Cl
• Plasma concentration plateaus and fluctuates about an average steadystate level. This is known as the plateau principle of drug accumulation.
• Steady-state is reached in 4–5 half lives .
• The amplitude of fluctuations in plasma concentration at steady-state
depends on the dose interval relative to the t½, i.e. the difference
between the maximum and minimum levels is less if smaller doses are
repeated more frequently.
• Drugs with short t½ (upto 2–3 hr) administered at conventional
intervals (6–12 hr) achieve the target levels only intermittently and
fluctuations in plasma concentration are marked. In case of many drugs
this however is therapeutically acceptable.
• For drugs with longer t½ a dose will accumulate according to plateau
principle and produce toxicity later on.
• Such drugs are often administered by initial loading and subsequent
maintenance doses.
• This is a single or few quickly repeated doses given in the beginning to
attain target concentration rapidly.
• It may be calculated as:
Loading dose = Vd x Css
• This dose is one that is to be repeated at specified intervals after the
attainment of target Css so as to maintain the same by balancing
elimination.
• It may be calculated as:
Maintenance dose= CL x Css x ΔT
• If there is no urgency, maintenance doses can be given from the
beginning.
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By prolonging absorption from site of administration
By increasing plasma protein binding
By retarding rate of metabolism
By retarding renal excretion
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Side effects
Toxic effects
Tolerance and tachyphylaxis
Idiosyncrasy
Drug allergy
Photosensitivity
Drug dependence - Psychological dependence / Physical dependence
Drug withdrawal reactions
Teratogenicity
Mutagenicity
Carcinogenicity