Pharmacokinetics

Dr. Marslin Gregory

Quantitative study of drug movement in,
through and out of body
 Pharmacokinetics (PK) &
pharmacodynamics (PD)

• PK - What the body does to the drug?

– Absorption; distribution, metabolism,
excretion (ADME)

• PD - What the drug does to the body?

– Drug concentration at the site of action or
in the plasma is related to a magnitude of
effect
 What is clinical
pharmacokinetics ?
• Study of the time course of a drug’s
movement through the body.

• Understanding of what the body does to (or

with) the drug.

• Application of Therapeutic Drug Monitoring

(TDM) and individualisation of drug therapy.
 Pharmacokinetics
• Absorption
• Distribution
• Metabolism
• Elimination
 Study of [drug] over time

The absorption of drug involves its passage of drug across cell membrane
 Transportation
Passage of drug actoss cell membrane

• Drugs are transported through

– Passive diffusion
– Filteration
– Specialized transport
 Transportation : Passive diffusion
• Drug diffuses from higher
concentration to lower
concentration across the
membrane.
• Lipid soluble drugs – dissolving
lipoidal matrix of membrane.
• Diffusion will depend on
– Lipid solubility of drug
– Difference in concentration
– pH of tissue
 Transportation : Filtration
Only water soluble substance can transported by this process

• Passage of drug across

the aqueous pores in
the membrane or
through the para-
cellular spaces.
• Lipid insoluble drugs
crosses membrane
– Size of pores and drug
molecule
Specialized Transport
 Specialized : Carrier Transport
• Transmembrane protein
– carriers and
transporters for
physiologically important
ions, nutrients,
metabolites,
transmitters
• Beside this they also
translocate xenobiotics
including drugs
metabolites
• Specific for the substrate
 Specialized : Carrier Transport
1. Transmembrane protein binds with their
substrate transiently.
2. Conformational changes – carrying the
substrate to the other side of membrane.
3. Dissociates
4. Return back to its original position
 Specialized : Carrier Transport
• Depending on the requirements of energy
– Facillated diffusion
– Active transport
• Primary active transport
• Secondary active transport
Carrier Transport : Facilitated diffusion
• Belongs to super family of
solute carrier (SLC)
transporter
• Operates without need of
energy – transport in the
direction electrochemical
gradeint
• Higher to lower
concentration
• Ex: glucose in muscle and
fat cells by GLUT 4
Carrier Transport : Active transport
• It requires energy and acts
against the electrochemical
gradient
• Selective accumulation of
solutes on 1 side
• Inhibited by metabolic
poison
Ex: levodopa and methyl dopa
absorbed from the gut -
aromatic amino acid
transport
 Specialized transport : Endocytosis
• Very little importance to the drug
translocation
• Large protein molecules and other metabolic
waste
 Absorption
• Movement of drug from its site of administration into
circulation
• Not only amount of absorption but also rate of
absorption is important
• Except when given i.v., the drug has to cross biological
membrane which is governed by following factor
– Aqueous solublity
– Concentration
– Area of absorbing surface
– Vascularity of absorbing surface
– Route of administration
 Bioavailability
• A concept for oral administration
• Useful to compare two different drugs or different
dosage forms of same drug
• Rate and extent of absorption of a drug
• Fraction of administered drug that reaches systemic
circulation in unchanged form
• Bioavailablity by i.v. is 100 % but by other routes it
decreases to some extent
– Incompletely absorbed
– First pass metabolism
– Sc/im – local binding
 Bioavailability
• Bioavailability is not a characteristic solely of
the drug preparation: variations in
– enzyme activity of gut wall or liver,
– in gastric pH or
– intestinal motility all affect it.
Distribution
 Distribution
• Once the drug has gained access to blood it gets
distributed to other tissues
• the extent of distribution of a drug depends on:
– Lipid solublity
– Ionization at physiological pH
– Extent of binding to plasma
– Tissue protein : Fat
– Difference in regional blood flow
– Disease like CHF, Uremia, cirrhosis
 Apparent volume of Distribution
• Volume that accommodate all
the drugs in body, if the
concentration throughout was
same as in plasma
V = dose administered/plasma drug
concentration

Intravascular Extracellular Uniform Intracellular

 Blood Brain barrier
• Capillary endothelial cells
in brain have tight
junction and lack large
intercellular pores and
above that there is layer
of neural tissue – Blood
brain barrier.
• In Choroid plexus,
capillaries are lined by
choroidal epithelium with
tight junction – blood-CSF
barrier
 Blood Brain barrier
• Both this membrane allows lipoidal drug and
limit the entry of non-lipoidal drug. Ex:
streptomycin, neostigmine.
• Beside this,
– P-gp and anion transporter (OATP) extrude drugs
from brain.
– Enzymatic BBB : monoamine oxidase (MAO),
cholinesterase and some other enzymes – inhibit
catecholamines, 5-HT, acetylcholine
• Ex: Dopamine doesn’t enter but its percursor
levodopa does.
 Placental Barrier
• Placental membrane is lipoidal and allows free
passage of lipophillic drugs, while restricting
lypophobic drugs.
• But higher concentration of lypophobic drugs
in maternal circulation – gain access to foetus.
• Beside this
– Placental efflux – P-gp
– Influx transporter
Metabolism
 Metabolism
Also known as biotransformation
• Chemical alteration in the body
• Causes loss of biological activity and thereby
excretion via renal route – increases
hydrophilicity
• Primary site of drug metabolism – liver
– Kidney, intestine, lungs and plasma.
 Biotransformation
– Activation – few drugs are administered in inactive
form (PRODRUG) and needs to be activated to form
active metabolite
• Stablity
• Good bioavailability
• Less side effect or toxicity
• Desirable pharmacokinetic properties
Ex: Morphine, cefotaxime, codeine, amitriptyline, digitoxin,
diazepam, losartan
– Inactivation – active metabolite and most drugs are
inactivated. Ex: Ibuprofen, paracetamol, lidocaine,
chloramphenicol, propranolol.
Excretion
 Excretion
• Passage out of systemically absorbed drug,
• Its excreted in
1. Urine
2. Faeces
3. Exhaled Air
4. Saliva & sweat
5. Milk
 Excretion : Urine
• Most important channel for excretion of
drugs.
• It eliminates water soluble substances.
• Amount of drug or its metabolites depends on
– Glomerular filteration (GFR)
– Tubular Resorption (TR)
– Tubular Secretion (TS)

Net Renal Excretion = (GFR+TS) - TR

 Excretion : Faeces
• Most of it derived from bile
• Large molecular drug is transported by this
route
• Deconjugation by glucouronide drug
• Ex: Erythromycin, ampicillin, rifamipin,
tetracycline, oral contraceptives,
phenolphthalein
• Drugs gets directly eliminated – anthracene
purgatives, heavy metals
 Excretion
Exhaled air
• Gases and volatile drugs or paticulate matter –
irrespective of lipid solubility
• Alveolar transfer of gas – partial pressure in
blood
• Ex: G.A., paraldehyde, alcohol
Saliva & Sweat
• Minor importance for drug excretion
• Ex: Lithium, pot. Iodide, rifampin and heavy
metal
 Excretion : Milk
• Important for infant sucking milk of mother on drug
• Most of drug enter – breast milk by passive diffusion
• Lipid soluble and PPB drugs do it better
• % of drug reaching infant is very less – majority of
drugs can be given to lactating mothers without ill
effect
• But lactating mother should be prescribed with drugs
with caution
• Contraindicated drugs : Amidarone, Anthraquinone,
Chloramphenicol, Ciprofloxacin, cyclosporine,
indomethacin, methotrexate, tetracyclin
• Special precaution : Ampicillin, aspirin, losarton,
metaclopromide, sulfonamide
Kinetics of Elmination
 Pharmacokinetics Parameters
• Bioavailability (F) : Fraction of administered drug that
reaches systemic circulation in unchanged form
F = amt. Of drug that enters systemic circulation (AUC)
Dose administered
• Volume of Distribution (V): Volume that accommodate
all the drugs in body, if the concentration throughout
was same as in plasma
V = dose administered/plasma drug concentration
• Clearance (CL) : the volume of plasma containing the
total amount of drug that is removed from the body in
unit time
CL = Rate of elimination/C
 Rate of elimination
• 1st order Kinetics : most of the drug
– Rate of Elimination of drug is directly proportional
to drug concentration
– CL remains constant
• Zero order kinetics : few drugs
– Rate of elimination remains constant irrespective
of concentration
– CL decreases with increase of concentration
– Constant amount of drug is eliminated in unit time
 Plasma Half Life
• Half-life = time required for serum plasma
concentrations to decrease by one-half (50%)
• Mathematically
t ½ = 0.693/k
k = elimination rate constant i.e fraction of total
amount of drug removed per unit time
k = CL/V
• Complete drug elimination can occur in 4-5
half life
 Steady Plasma concentration
• Steady Plasma concentration (Cpss) –
repeated drug administration at relatively
short interval of time
• Input of drug balance = clearance
Cpss = dose rate/CL
From this equation, it is clear that dose rate can
be calculated if CL and target Cpss of drug is
known.
 Steady Plasma concentration
• Earlier equation is valid for drug route
administration where the bioavailability (F) is
100 %, but where it falls short the equation
turns to be
dose rate = (target Cpss X CL)/ F
Both this equation stands valid for the drugs
following 1st order kinetics
 Michelis Menten Kinetics
• Elimination changes from first order to 0 order
over the therapeutic range.
• This signifies that till the saturation level of drug,
Cpss is related to dose rate.
• But it turns out of proportion beyond it
Rate of drug elmination = (Vmax) (C) / Km + C
Km = plasma conc. at which elimination rate is half
maximal
C = plasma concentration of drug
Vmax = maximum rate of drug elimination
Ex: Phenytoin
Plateau Principle of drug accumulation
• When constant dose of a drug is repeated
before the expiry of 4 t ½ , it would achieve
higher peak concentration, because some
remnant drug will be present in the body.
• Subsequently plasma concentration becomes
constant and forms a plateau and fluctuates
around desired therapeutic level of drug.
• Desired therapeutic level reaches 4-5 half lives
After every 4-5 half life the drug concentration falls to almost
3-4 %
So if the dose is repeated before the expiry of 4-5 half life, the
concentration of drug keeps on increasing after every
subsequent dose.
 So its better to administer the drug in small dose over small
regular interval rather than large dose in large interval of time
 Target Level Strategy
Target Level Strategy Example
Narrow safety margin with Range of therapeutic Anticonvulsant,
unquantified concentration antidepressant, lithium,
pharmacokinetic data antirythmics, theophyline
and some antimicrobials
Short half life Conventional interval (6-12 Penicilllin, amipicillin,
hrs) – fluctuating plasma chloramphenical,
concentration erythromycin, propranolol
Long half life Daily/weekly/Single dose MAO inhibitors, reserpine,
omeprazole
Steady drug concentration Loading Dose and Steroids
maintenance dose
 Loading Dose
• Single or few quickly repeated dose to attain
target concentration rapidly
Loading dose = (target Cp x V )/ F
So loading dose is governed by V not CL or half life
of drug
 Maintenance dose
• The amount of drug given to maintain the
steady state plasma concentration (Cpss) of
drug at regular interval so as to balance the
elimination.
dose rate = (target Cpss X CL)/ F
So its dependent on CL or half life of drug
 Therapeutic drug monitoring (TDM)
• Cpss of a drug depends on its F, V and CL –
each of this parameters varies from patient to
patient
• Measurement of plasma concentration of
drug after initial drug administration (based
on average patient) can give all this parameter
of a individual
• This helps for the subsequent quantification of
drug dose regimen
 Use of TDM
• Low safety margin – digoxin, anticonvulsants,
antiarrythmics, theophylline, aminoglycerides,
lithium, TCA
• If individual variation are large – antidepressant,
lithium
• Potentially toxic drug used in renal failure –
aminoglycoside antibiotics, vancomycin
• In case of poisoning
• Failure of response without any reason
• Check patient compliane
 Prolongation of drug action
• Frequency of drug administration
• Improved patient compliance
• Large fluctuation of plasma concentration
should be avoided
• Drug effect could be maintained overnight
without disturbing sleep
All drugs cant be made long acting, Ex:
Sedatives, headache remedy) or longer acting
drugs
 Method to achieve this objective
• Prolonging the absorption from site of
administration
– Entral : Sustained relase tablets, spansules
– Parentral: Insoluble form (oily), pellet implantation,
sialistic and biodegradable implant, inclusion of
vasoconstriction
– Transdermal patches
• Increasing plasma protein binding
• Retarding metabolism
• Retarding elmination
 Refrences
• Essential of medical Pharmacology 4th edition –
KD Tripathi
• Rang_and_Dales_Pharmacology__6th_Ed_2007
• Pharmacology and Therapeutics for Dentistry, 6th
Edition
• Color Atlas Of Pharmacology, 2Nd Ed (Lüllmann,
Thieme 2000)
• Bertram G. Katzung-Basic & Clinical
Pharmacology(9th Edition)
• Google generated subsequent sites