PHARMACOKINETICS

Mr. Manikanta
•P.K is the study of A,D,M,E of drugs.“what the body
does to the drug.”
•i.e. Movement of drugs into, within & out of the
body.
•Drug to produce a specific response –needs a
adequate conc. +nt at the site of action.
•Once the drug is adm-
 It is absorbed, i.e. enters the blood,
Distributed to different parts of the body,
 Reaches the site of action,
Its metabolised & then excreted finally.
Biotransportation -Movement or Translocation of drug
molecules from one side of biological barrier to other.
Major Transport mechanisms:-
 Passive /simple diffusion
 Carrier mediated transport
o Facilitated diffusion
o Active transport
 Pinocytosis/ phagocytosis
 Filtration
 Passive Diffusion
•The drug molecules- higher conc. to lower conc.
•Energy is not required.
•Nonionised / lipid soluble drugs –rapidly diffuses(pH
independent).
•Acidic drugs- are Nonionised in acidic media & absorbed
from stomach -e.g. Phenytoin, Salicylates.
•Basic drugs- are Nonionised in alkaline media & absorbed
from intestine. e.g. morphine, atropine etc.
Simple diffusion
 Facilitated diffusion-

• Carrier/Transporter moves the drug along its Conc. gradient.

• Energy is not required.

 Facilitated diffusion
membrane Lower conc.
Higher conc.

carrier
Drug

Drug

Carrier
+
Drug
 Active transport-(up hill transport)-

• Energy dependent C.M.T- against conc. gradient.

• Energy is required.

• Drugs related to natural metabolites are transported by this

process- L.dopa. iron, amino acids.

• Drugs competing for the same transporter may interfere

with drug movement.

e.g., Penicillin + Probenecid during excretion.

 Active Transport

Higher conc. Membrane Lower conc.

Carrier Drug

Drug
Energy

Carrier
+
Drug
 Pinocytosis(uptake of fluid)-

• It’s a process where a cell drink or engulfs a fluid or a drug

in a solution. E.g. insulin-BBB.

 Phagocytosis (uptake of particles)- Phagos = eat.

• Some particles are transferred by local invagination of C.M.

E.g. Botulinum toxin & allergic reactions-energy is utilized.

 Filtration-

• Filtration is a passage of drugs through aqueous pores /

paracellular spaces of CM.

 Absorption- Movement of the drug into the blood stream

from the site of administration. Absorption via GIT/
parental sites/lungs topical sites.

• For the drug to reach its target site, should pass through the
membranes.

• Absorption is imp. for all the routes except I.V routes.

 BIOAVILABILTY-
• The rate & extent to which the active concentration of the drug is
available at the desired site of action (target site).
• Rate & extent of absorption-influences the clinical effectiveness
of drugs.
• Variation in B.A may to toxicity/ therapeutic failure.
e.g., Drugs with low safety margin & such drugs needed dose
adjustment.(corticosteroids, anticoagulants).
• For such drugs, in a given Pt, the preparations from single
manufacture should be used.
 Bioavailability

Bioavailability AUC (Oral)

= X 100
AUC (IV)

Destroyed Not Destroyed Destroyed

in gut absorbed by gut wall by liver
Oral/Dose
to
systemic
circulation
Several factors influencing the rate & extent of
absorption / B.A. they are-
1. Disintegration & dissolution time
2. Formulation
3. Particle size
4. Lipid solubility
5. PH & ionization
6. Area & vascularity of the absorbing surface
7. Gastrointestinal motility
8. Presence of food
9. Diseases
10. Metabolism
 DRUG

Disintegration

To fine particles

Dissolution

…..
… Drug in solution
…
…
……
…..
……

Available for
absorption through
GIT
First pass metabolism-means drug degradation occurs
before the drug enters into S.circulation.

- Gut wall & liver.

- Pre-systemic metabolism.

- Characteristic feature of oral route.

- B.A of orally adm. & therapeutic response

 First pass metabolism

Oral administration

Stomach
Bile juice
Duodenum
FIRST PASS

Liver

Small intestine
-Extent of 1st.pass depends on drug & the individuals from
partial to total inactivation.

-Partial can be compensated by giving higher dose.

- e.g. L-dopa, morphine, GTN, Isosorbide dinitrate &

Propranolol.

- Complete 1st.pass- change the route of adm.(sublingual)

- e.g. isoprenaline, hydrocortisone, insulin.

- B.A of many drugs is in pts with liver disease-

hepatic metabolism .
e) Drug-Drug interactions-
• Liq. Paraffin (emulsification)- Vit.A

• Antacids (Al,Mg,Ca,) & haematinics -T.Cs.

• Barbiturates(E.induction)- many drugs.

• Probenecid (transport blocker)-Penicillin.

 DISTRIBUTION

Drug administration

Bio-transportation Absorption

Distribution Metabolism

Excretion of drugs
Drug distribution(D) means pattern of “scattering” of

the specified amount of drug among various locations within the body.

• Once the drug absorbed into bloodstream, it gets distributed to all

organs or tissues.

• After absorption the drug may

 bind to R – target site of action,

 bind to plasma Ptns,

 accumulate in various storage sites Or

 enter into tissues which are not involved in 10 site of action (i.e.,
involved in metabolism & excretion).
 Free/un-bound fraction of drug:-

-Pharmacologically active

-Available for action, metabolism, excretion.

-It can pass through the capillary wall & BBB,

-Excreted through glomerulus, saliva, CSF & milk.

 When free dugs level falls/eliminated from body, more drug

dissociates from the drug-plasma Ptn complex.
Ptn bounded drug acts as a-

 Cellular reservoir

 Pharmacologically inactive

 Prolongs drug duration

 Drug remains in blood as it can’t pass thru’ membranes.

 Delays drug metabolism & excretion

 Decreases drug clearance & can’t be removed by hemodialysis.

 Diminishes drug penetration into CNS.

 Responsible for drug displacement interactions(toxicity).

Tissue Storage Sites Drug

Sk.muscle & Heart Digoxin, Emetine (Muscle Ptns)

Liver Chloroquine, Mepacrine, Tetracyclines, Emetine,
Digoxin
Kidney Digoxin, Chloroquine, Emetine

Thyroid Iodine.
Retina Chloroquine

Brain Acetazolamide, Isoniazid, Chlorpromazine.

Bone & Teeth T.C’s, Heavy Metals

Adipose Tissue Thiopentone, Ether, Minocycline, DDT

Blood brain barrier (BBB)-

• Only lipid soluble/ unionised drug can cross the BBB.

• During the meningitis, the barrier is more permeable to

drugs. e.g., Penicillin.

• BBB is weak at certain areas like CTZ & allows some

drugs to diffuse.
Placental barrier -

• Lipid soluble, non-ionised drugs readily cross the placenta

while water soluble/ionised drugs cross to a lesser extent.

• Thus drugs taken by mother can cause several unwanted

side effects.
METABOLISM/ BIOTRANSFORATION-

• Is a process of biochemical alteration of the drug in the

body.

• Our body tries to convert them into inactivate form/polar

compounds- easily excreted through kidneys.

• Some drugs are excreted largely unchanged in the urine-

e.g., Furosemide & atenolol.
• Sites

– Major site of biotransformation- Liver

– Minor sites -Kidney, gut mucosa, lungs, blood & skin.

 Metabolism (biotransformation)
Biotransformation

Active Drug
Metabolism

Inactivation active
metabolite
(duration of
active action gets
metabolite prolonged)
Inactive Drug
(Prodrug)

Active Drug
 Metabolism
Consequence of biotransformation

Active drug to Active drug to active Inactive drug to active

inactive metabolite metabolite metabolite (prodrug)

e.g. Morphine e.g. Primidone e.g. Levodopa Dopamine

Phenobarbitone

Chloramphenicol Digitoxin Digoxin Prednisone Prednisolone

Diazepam Oxazepam Enalapril Enalaprilate

46
 PRODRUG

It is an inactive form of a drug, which is converted to an

active form after metabolism
• Improves drug B.A
• Prolongs the duration of action
• Provides site specific drug delivery
• Less side effects
Important drug biotransformation reactions

Reactions Examples of drugs

Phase I - reactions
Oxidation Phenytoin, Diazepam, Ibuprofen, Amphetamine,
Chlorpromazine, Dapsone

Reduction Chloramphenicol, Halothane

Hydrolysis Pethidine, Procaine

Phase II – Conjugation reactions

Glucuronide conjugation
Acetylation
Methylation
Glutathione conjugation
Sulfate conjugation
Aminoacid conjugation
Chloramphenicol, Morphine, Diazepam, Aspirin
Sulfonamides, Isoniazid
Adrenaline, Noradrenalin, Dopamine, Histamine
Paracetamol
Paracetamol, Steroids
Salicylic acid, Benzoic acid
 Enzyme
Induction
• Microsomal enzymes are located in the S.E.R of liver cells

• Certain drugs & environmental pollutants increases the

synthesis of these catalytic enzymes- called enzyme
induction.

• It speeds up metabolism of the inducing drug itself, and

other drugs metabolized by the microsomal enzymes

– E.G., Phenobarbitone, rifampicin, alcohol, cigarettes,

some enzyme inducers
 Clinical relevance of enzyme induction

1. Drug interaction

 Therapeutic failure- O.C pills X Rifampicin.

 Toxicity- Rifampicin X Paracetmol.

2. Tolerance to drugs- Carbamazepine-induces its own

metabolism.

3. Result in disease- Ppt of Acute intermittent Porphyria.

4. Therapeutic use of enzyme induction-

- Rx of kernicterus, Cushing's syndrome, Chronic poisoning &

liver diseases.
 Enzyme inhibition

– Some drugs inhibit microsomal enzyme activity.

– Drugs like Cimetidine & Ketoconazole bind to these

enzymes & thus competitively inhibit metabolism of
endogenous substances like testosterone & other drugs
given concurrently.

– Enzyme inhibition is the basis for drug interactions.

E.g.,: erythromycin, Ketoconazole, ciprofloxacin,

verapamil are some enzyme inhibitors
Excretion-

• Drug are excreted from the body after being converted to

H2o soluble metabolites while some are directly eliminated
without metabolism.

• Major organs- kidneys, intestine, biliary & lungs.

• Minor routes- saliva, sweat & milk.

Example of drugs that could be toxic to the suckling infant when
taken by mother
Sulphasalazine Theophylline Anticancer Salicylates
drugs
Chloramphenicol Nalidixic acid Doxepin Aminodarone

Primidone Ethosuximide Phenobarbitone Phenothiazines

Renal elimination is determined by

1. Glomerular Filtration

2. Active Tubular Secretion

3. Passive Tubular Reabsorption.

 Tubular Reabsorption (TR): occurs in the distal tubules by
passive diffusion.

• TR is depends on lipid solubility, ionization & urine PH.

Weakly acidic drugs:-

• If pH of urine is acidic, acidic drugs remain unionized & get

reabsorbed.

• If pH of urine is basic, acidic drugs become more ionized

& reabsorption is retarded & facilitates excretion.
Weakly basic drugs:-

• If pH of urine is basic, basic drugs are more reabsorbed.

• If pH of urine is acidic, basic drugs are more excreted.

• No reabsorption for strong acidic or basic drugs

• Quaternary ammonium salts & A.G’s are being highly polar

--- not reabsorbed.
• Biliary excretion--drugs & bilirubin from plasma to bile.
E.g. quinine, erythromycin.

• E.H.C- E.g. Digitoxin.

• Fecal elimination:e.g.Mgso4, Streptomycin, Bacitracin .

• Alveolar excretion: Gases, volatile liquids of G.A, Alcohol.

• Milk: Milk is more acidic than plasma, basic drugs are

easily excreted than acidic. e.g., Chloramphenicol,
chloroquine, primaquine, cotrimoxazole.
• Griseofluvin -keratin

• Arsenic, mercury-hair follicles

• Iodine, KI, Li, phenytoin-saliva

• Urea derivatives-sweat.
Clearance: the clearance of a drug is the theoretical volume of
plasma from which the drug is completely removed in unit
time.

CL = rate of elimination/plasma conc.

• Plasma half life: is the time taken for the plasma

concentration of the drug to be reduce to half of its value.

• 4-5 half lives are required for complete elimination of a

drug.

• Each drug has its own elimination t1/2 & gives an idea
about duration of drug action.
Thank u