Pharmacokinetics

1. Prepared by-
Tanvir Ahmed Fahim
Id : 181008
Dept. of Pharmacy
Jashore University Of Science And Technology
Jashore, Bangladesh
Pharmacology
Topic : Pharmacokinetics

2. Pharmacokinetics
▪ The word "Pharmacokinetics" is derived from Greek words
Pharmakon (drugs) & Kinetics (movement).
▪ It is the study of absorption, distribution, metabolism &
excretion of drugs.
▪ Simply means , "What the body does to the drug."
▪ It determines -
1. Routes of drug administration.
2. Dose.
3. Onset of action.
4. Duration of action.
5. Cmax
6. Tmax.

4. ▪ Referred to all types of cell membrane of the body.
This is first introduced by Singer & Nicholson in 1972. Biological
membranes are present in capillaries except cerebral capillary &
GIT. They have a hydrophilic polar head & hydrophobic nonpolar
tail. Drug molecules cas pass the biological membrane in
unionized form only.
▪ Characteristics :
1. Thickness : 80-100 Å
2. Structure :
a. Lipid bilayer : Composed of lipid & cholesterol. Extrinsic & intrinsic
b. Embedded proteins : These may be integral or peripheral. The
protein may acts a a receptor, transporter or enzyme.
c. Acqueos pores : The protein contains pores through which drugs are
absorbed by aqueous diffusion.
Biological membrane

6. ▪ It is the process by which drug enters into the circulation
from its site of administration across the biological
membrane.
▪ Sites of drug absorption :
1. GIT - Stomach, small intestine, rectum.
2. Respiratory tract.
3. Muscle & subcutaneous tissue.
4. Skin
Absorption

7. 1. Routes of drug administration : Absorption rate- IM>SC>Oral
2. Dosage formulation : Absorption rate- Syrup>Capsule>Tablet
3. Lipid solubility of drug : more lipid solubility= more absorption.
4. Water solubility of drug : more water solubility=less absorption
5. Mol. wt of drug : less the mol wt. = greater the absorption.
6. Size of the drug : less the size = greater the absorption
7. Conc. gradient across the biological membrane : greater the conc.
gradient = greater the absorption.
8. Absorbtive surface area : Stomach=less surface area=less absorption ;
Intestine = more surface area=more absorption.
9. Presence of another drug/food decreases the absorption.
9. pH of absorptive media :
Factors influence drug absorption

8. ▪ Most of the drugs are weak electrolyte (weak acids or bases) &
their ionization is pH dependent. However, strong electrolyte
completely dissociates.
▪ The ionization of weak electrolyte are given by the equation:
pH = pKa + log [protonated form] / [unprotonated form]
This equation relates the pH of the medium around the drug &
the drug’s acid dissociation constant (pKa) to the ratio of the
protonated (HA or BH+) & unprotonated (A– or B) forms.
▪ At steady state, an acidic drug will accumulate on the more
basic side of the membrane and a basic drug on the more acidic
side—a phenomenon termed as ion trapping.
Influence of pH on drug
absorption

9.  The weak acidic drug is absorbed at a faster rate from the stomach,
thus is because the acidic substance can't be ionized in acidic
medium. So, the unchanged substance can easily be passed due to its
lipid solubility. Likewise, waek basic drugs are absorbed at a faster
rate from the intestine.
 pH of absorptive media :
Acidic drug in low pH : less ionization = More absorption
Basic drug in low pH : Greater ionization = less absorption
Acidic drug in high pH : Greater ionization = less absorption
Basic drug in high pH : less ionization = More absorption
[ Point to remember : The drugs which are Unionized, low polarity & higher lipid
solubility are easy to permeate membrane.
The drugs which are ionized, high polarity & lower lipid solubility are difficult to
permeate membrane.]
Influence of pH on drug absorption

10. 1. Passive transport :
a. Passive diffusion.
b. Filtration
2. Special transport :
a. Carrier mediated -
l) Active transport. (primary & secondary)
ll) Facilate diffusion.
b. Endocytosis
Process of drug absorption

11. ▪ It is defined as the movement of drug molecules across the biological
membrane towards the concentration gradient.
▪ Criteria of passive diffusion :
1. Commonest process of drug absorption.
2. Lipid soluble drugs are diffused in the lipoidal matrix of the
membrane
3. Diffusion rate is proportional to the concentration gradient across
the cell membrane.
4. After a steady state is attained, the concentration of the unbound drug
is the same on both sides of the membrane.
4. It depends on size of molecules.
5. No need of energy. 6. No need of carrier.
6. It's a slow process.
7. It Obeys Flick's principle & law of mass action.
8. The drugs moves from a region of high conc to one of a lower conc.
Passive diffusion

12. ▪ Defined as the movement of drug molecules that occur through the
aqueous pores of the biological membrane.
Filtration process can be accelerated if the hydrodynamic flow of
solvent occurs under hydrostatic or osmotic pressure gradients.
Sites of filtration : Glomerulus of kidney, capillaries.
Ex - Urea, alcohol, oxytocin.
▪ Criterias :
1. It depends on the size of molecules & flow of blood.
2. Majority of the cells have small aqueous pores & drugs having
molecular wt. above 100 daltons can't pass through the pores.
3. Lipid insoluble drugs transporfed if their molecule ire smaller than
the aqueous pores.
4. No need of energy. 5. No need of carrier.
Filtration

13. ▪ Defined as the movement of drug molecules through the
biological membrane against concentration gradient by the
help of carrier protein with active expenditure of energy.
Examples : AA, electrolytes, levodopa, streptomycin.
▪ Sites of active transport :
Renal tubular cell, GIT, Biliary tract, Blood-brain barrier.
▪ Criteria of active transport :
1. Occurs against the concentration gradient.
2. Natural metabolites are actively absorbed.
3. It exhibits selectivity & saturability.
4. Expenditure of energy is required.
5. Carrier protein is required.
6. It's a rapid process.
Active transport

14. ▪ Depending on the source of driving force there are 2 types of active
transport :
1. Primary active transport: Energy is obtained directly by the
hydrolysis of the ATP
2. Secondary active transport : Energy is derived from the downhill
movement of another solute. It's further divided into-
a) Co-transport(Symport)- when both the solutes move in the same
direction.
b) Exchange transport(Antiport)- when both the solutes move in
the opposite direction.
Active transport

15. Active transport

16. ▪ Defined as the movement of drug molecules through the
biological membrane which is facilated by a macromolecule.
Examples - Glucose, VitB12 absorption, Fat soluble vitamins.
▪ Criteria of facilitated diffusion :
1. Occurs against the concentration gradient.
2. Depends on the difference in concentration of drugs on two
sides of the membrane
3. It's Saturable process.
4. No energy is required .
5. Carier protein is required.
6. Quicker process than passive diffusion.
Facilitated diffusion.

17. ▪ When the membrane engulfs the drug molecule by making a
pseudopod is called endocytosis.
▪ Types of endocytosis :
1. Pinocytosis : Engulfs water i.e. cell drinking.
2. Phagocytosis : Engulfs other than rater. i.e. cell eating.
▪ Pinocytosis : This is the process of transport drug molecules through
the membrane in particulate form by formation of vesicles.
Ex : aminoglycoside antibiotics.
Larger molecules like protein are transported by this process.
Endocytosis

18. ▪ Oral Route:
a) Effective barrier:
Epithelial lining; rate of absorption is proportional to their lipid-water
partition co-efficient.
Acidic drug like aspirin, salicylates etc absorbed well from stomach,
Basic drug like morphine, atropine, quinine etc. absorb well form
duodenum.
b) Acidic drug absorption from stomach is less due to -
 Thick mucus membrane
 Small surface area
 Slow dissolution
c) Certain drugs degrade the acidic environment of stomach e.g.
Pen-G, Insulin, Cephalosporin etc.
Enteric coating or surface coating or other sustained release product
free from such draw back.
Effect of route of administration on
drug absorption

19. d) Absorption is effected by presence of food due to :
 Dilution of drugs
 Delay emptying
 Drug-food interaction
e) Effected by drug-drug interaction..
f) Effected by alteration of intestinal microbial flora or GUT wall
motility
e.g. Anticholinergic, morphine - relaxes gut wall ;
Neomycin, Vinblastine - damage the mucus membrane.
Effect of route of administration
on drug absorption

20. ▪ Subcutaneous:
Drug those can not absorbed through oral route can absorbed
through IM or SC
Drug deposited directly into the vicinity of the capillaries. Lipid
soluble drug directly passes across the whole surface of the
capillary membrane.
Capillaries are highly porous- do not obstruct ionized
molecules, even large molecules are absorbed through
lymphatic system.
SC absorption is slower then IM.
But both are faster than oral route.
Massage or application of heat accelerate the absorption.
Effect of route of
administration on drug
absorption

21. ▪ Topical site:
Depending on the lipid solubility of the drugs.
Only few drugs can penetrate through the intact skin, e.g.
nitroglycerin, hyoscine, estradiol.
Corticosteroid- applied over skin can have systemic effect
and pituitary adrenal suppression.
Absorption can be promoted by rubbing the skin, also
incorporation of smoothening agent or
vasodilating agent enhance absorption.
Abrasive surface – accelerate the absorption process.
Effect of route of administration
on drug absorption

22. ▪ The fraction of unchanged drug reaching the systemic
circulation by administration of any route is called
Bioavailibility.
▪ Bioavailibility of a drug is represented by %. Different routes of
drug administration have different bioavailibility. Drugs given by
intravenously have bioavailability almost 100%.
▪ Ex - If a 500 mg tablet is administrated orally & 400 mg of
tablet reaches to systemic circulation, then 400 mg is the
bioavailibility of the tablet.
In this case, the bioavailibilty factor will be :
<F> = 400/500 = 0.8
Bioavailability

23. ▪ Variation in Bioavailability :
1. Routes of administration : Bioavailibilty is 100% from IV route but
lower after oral ingestion due to incomplete absorption or 1st pm.
IV> IM=SC > Rectal > Oral
2. Physical state & particle size :
a. Physical state : liquid>solid.
b. Particle size : crystalloid>colloid.
3. Variation in formulation :
a. Disintegration time : more the disintegration time, less absorption &
less bioavailability .
b. Dissolution time : more the dissolution rate, more the bioavailibilty.
4. Manufacturing variability : excipients used in the formulation may
affect bioavailability.
Bioavailability

24. Difference in bioavailability seen with poorly soluble drugs. Reduction
of particle size will enhance drug solubility by increasing the surface
area-increase bioavailability-reduces the dose size.
e.g. the dosage of Griseofluvin and Spironolactone can be reduced to
its half of the quantity while given in micro fine powder form.
Bioavailability

25. Bioavailability

26.  Therapeutic range : The range of drug level in which a drug
has the desired effect upon the body.
 MEC (minimum effective conc) : The minimum concentration
of drug needed to produce the desired pharmacological effect.
 MTC (minimum toxic conc) : The minimum concentration of
drug needed to produce a toxic effect.
 Onset time : The time required for the drug to reach the
MEC/ exert a pharmacological effect.
 Duration of action : The length of time that a particular drug
is effective.
 Cmax : The maximum conc. of drug achieved in blood plasma.
 Tmax : The time take to reach the Cmax.
Bioavailability

28. ▪ Drug distribution is a process by which a drug reversibly leaves
the bloodstream & enter into the interstitium or cell of the
tissues.
▪ The major sites of drug distribution :
Plasma, Interstitial fluid, Intracellular fluid, Transcellular fluid,
Fat.
Distribution

29. ▪ Factors influence drug distribution :
1. Lipid solubility : Lipid soluble drugs readily move through
membranes, hence their distribution is greater. But, lipid
insoluble drugs don't readily penetrate membranes,confined to
plasma, hence their distribution is less.
2. Regional Blood flow : Higher the blood flow, higher the drug
distribution is.
3 Plasma protein binding of drugs : High ppb of drugs reduce
the drug distribution & vice versa.
4. Tissue binding affinity : Greater the tissue binding affinity of
drug grater the drug distribution & vice versa.
5 pKa value of drugs : High pKa value of drug reduces the drug
distribution.
6. Diseases like CHF,urernia,cirrhosis reduce drug distribution.
Distribution

30. ▪ It's defined as the volume of fluid in which the drug is distributed
at the same concentration as in plasma. Expressed as Vd.
Vd = Total amount of drug/Plasma conc of drug.
▪Ex: Chloroquin – 13000 L, Digoxin – 420 L, Morphine – 250 L,
Streptomycin & Gentamicin – 18 L.
▪ Factors which influenced drug distribution are same to Vd.
▪ If a drug has high tissue binding affinity, then the plasma
concentration will be low and the Vd become very large. Drugs
having high Vd includes - Antidepressants, Digoxin, Chloroquine
etc.
▪ It's called apparent volume of distribution. `Vd` is an imaginary
Volume of Fluid which will accommodate the entire quantity of
the drug in the body, if the concentration throughout this
imaginary volume were same as that in plasma.
Volume of distribution

31. ▪ when a highly soluble drug is distributed into other tissues
from its site of action is called redistribution of drugs .
Greater the solubility of the drug greater is its redistribution.
▪ Highly lipid-soluble drugs given by IV or inhalation methods
are initially distributed to organs with high blood flow(like
brain,kidney,liver etc) .
Later, less vascular but more bulky tissues (like muscle, fat)
take up the drug & plasma concentration falls & the drug is
withdrawn from these sites.
If the site of action of the drug was in one of the highly
perfused organs, redistribution results in termination of the
drug action.
Redistribution

32. ▪Plasma protein binding refers to the process to which drug
molecules attach to the plasma proteins when the drug
appears in the circulation.
Usually, drugs bind with plasma protein by H bond, Ionic bond
or Vader-waals bond. Acidic drugs bind to Albumin & the basic
drugs bind to alpha1 glycoprotein.
▪ A drug in blood exists in two forms: bound & free. The free
drugs are active & able to distributed into another
compartments. But, due to drug's affinity for plasma
protein,the bound drugs become bind to plasma proteins. The
PPB fraction isn't available for its action.
Plasma protein binding

33. ▪ Cinical significance of PPB :
1. There is an equilibrium between PPB fraction of drug & free drug
2. High PPB restricts a drug into the compartments, So, the Vd became
less.
3. High PPB makes a drug long acting, because PPB makes the drug
unavailable for metabolism and excretion.
4. The binded drug with plasma protein doesn't exerts its action until the
dissociation of free drug occurs. So PPB acts as a temporary storage of
drugs .
5. The drugs with higher affinity for Plasma proteins can replace the
other Drugs with lower affinity. But acidic drugs cannot replace the basic
drugs & vice versa .
6. In case of hypo-albuminemia binding may be reduced & high conc. of
drug may be attained.
Plasma protein binding

34. ▪ The BBB is a highly selective semipermeable border that
separates the circulating blood from the brain and extracellular
fluid in the CNS.
The BBB results from the establishment of tight junctions between
endothelial cells in CNS vessels. At the interface between blood
and the brain, endothelial cells are stitched together by these tight
junctions. Tight junctions between the endothelial cells of the
blood capillaries are responsible for the BBB.
Blood brain barrier

35. Blood brain barrier

36.  The placenta is the interface between mother & fetus. Drugs
administered to mothers have the potential to cross the
placenta & reach the fetus.
 It is lipoidal in nature, thus allow free passage of lipophilic
drugs to the fetus & restrict only hydrophilic drugs.
 Placental P - glycoprotein serves to limit foetal exposure to
maternally administrated drugs.
 However, after long time existence of non-lipid soluble drug at
higher concentration in the maternal circulation, restricted
amount can penetrate into the placenta and can cause harm to
fetus.
 Thus, it is incomplete barrier and almost any drug can cross
and effect the fetus.
Placental transfer

37. ▪ Significance of BBB :
1. The BBB is highly selective, means it only allows certain
substances to cross from the bloodstream into the brain. This
functions to protect the brain from toxins, pathogens, and even
circulating neurotransmitters that can be potentially damage to
neurons if their levels get too high.
2. Lipid soluble drugs can readily penetrate BBB. It prevents entry of
lipis insoluble drugs.
3. Gases & water can also pass readily through the barrier.
4. Ionised or polar drugs fail to penetrate the CNS.
5. Protein bound drugs & other large organic molecules unable to
cross BBB.
6. Meningitis is an inflammation of the membranes that surround the
brain and spinal cord. This increase the permeability of the BBB &
hence increase the penetration of various substances including either
toxins, antibiotics into the brain.
Blood brain barrier

38. Drug may accumulate in specific tissue or organs.
Drug tend to store different tissue contribute to long duration of
action and larger V.
May cause local toxicity.
1. Heart and skeletal muscles – digoxin
2. Liver – chloroquine, tetracyclines, digoxin
3. Kidney – digoxin, chloroquine
4. Thyroid gland – iodine
5. Brain – chlorpromazine
6. Retina – chloroquine
7. Iris – ephedrine, atropine
8. Bones and teeth – tetracyclines, heavy metals
Tissue Storage

39. ▪ The biochemical alteration of drugs inside the body by the
action of enzymes is called biotransformation.
▪ Aims of biotransformation :
1. To make the drugs more water soluble & less lipid
soluble.
2 To promote excretion of drugs.
3. To convert inactive prodrugd into active drugs .
▪ The major organ of biotransformation is liver(99%). Others
are Lungs, Kidneys, Intestine, Plasma etc.
Biotransformation

40. ▪ Results of biotransformation :
The results of biotranformation is for the conversion of :
1. Active drugs into another active metabolites :
ex : Aspirin- Salicylic acid. Codeine- Morphine. Digitoxin-
Digoxin.
2. Active drugs into another inactive metabolites :
ex : Morphine - Morphine-3-glucoronide.
3. Inactive drugs to active drugs :
ex : Levodpa- Dopamine. Prontosil- Sulfonamide.
4. More toxic drugs into less toxic metabolites :
ex : Phenacitin- Acetaminophen.
Biotransformation

41. There are 2 phases of biotransformation :
1. Phase-l (non-synthetic) : convert the parent drugs to more polar
metabolites by introducing or removing th functional group(-OH,-
NH2,-SH).
Enzymes involve in phase-l are CYP-450, esterase, alcohol
dehydrogenase etc. The phase is catabolic in nature.
2. Phase-ll (synthetic) : Here the phase-l metabolites
undergo conjugation with an endogenous substance.
(like Glucoronic acid, acetic acid) to yield conjugate
drug which is polar & readily excretable through the
kidneys.
Enzymes involve in phase-ll are Sulfokinase, methyltrasferase etc. The
phase is anabolic in nature.
Process of Biotransformation

42. ▪ Phase-l reactions :
1. Oxidation : Involves in the addition of oxygen or removal of
hydrogen.
It is the main process of metabolism. It produces unstable
intermediates like epoxides, superoxides.
2. Reduction: Involves in the addition of hydrogen or removal of
Oxygen.
It's the opposite to oxidation.
3. Hydrolysis : This is cleavage of drug molecule by taking up a
molecule of water.
It occurs in liver, intestines, plasma & other tissues. Usually amides &
polypeptides are hydrolysed by amidases & peptidases.
4. Cyclization : Formation of ring structure from a straight chain
compound
5. Decyclization : Opening up ring structure from the compound.
Process of Biotransformation

43. ▪ Process-ll reactions :
1. Glucuronide conjugation: Compounds with hydroxyl or carboxylic
acid group are easily conjugated with glucuronic acid .
Examples: Chloramphenicol, aspirin, morphine, metronidazole,
bilirubin, thyroxine.
2. Acetylation conjugation: Compounds having amino or hydrazine
residues are conjugated with the help of acetyl CoA, e. g.
sulfonamides, isoniazid.
3. Sulfate conjugation: The phenolic compounds and steroids are
sulfated by sulfokinases, e.g. chloramphenicol, adrenal and other
steroids.
4. Methylation: The amines and phenols are methylated by
methyltrasferase. Methionine and cysteine act as methyl donors.
Examples: adrenaline, histamine, nicotinic acid.
Process of
Biotransformation

44. ▪ Micrisomal enzymes:
Located into the smooth endoplasmic reticulam of liver, lung,
kidney, & intestinal mucosa.
Ex- monooxygenase, cyt-P450, glucuronyl transferase.
They carry out most of the oxidation, reduction, hydrolysis and
glucuronide conjugation.
▪ Non- microsomal enzymes:
They present in the cytoplasm , mitochondria , plasma & other
tissues.
Ex. Flavoprotein oxidases, esterases
Reaction catalyze by them are some oxidation, many hydrolytic
reaction and all most all conjugation reaction
Drug metabolism enzymes

45. ▪ Elimination of drugs and its metabolites from the body through the
excretion organs is called drug excretion.
▪ There are 2 types of excretion :
Renal excretion & Non renal
excretion(biliary,pulmonary,salivary,mammary,dermal )
▪ Routes of drug excretion :
 Urine:
Most important channel of excretion for most of the drug. Excrete
through kidney
 Faeces:
Unabsorbed fraction are excreted.
Drug is absorbed - glucuronidated or sulfatated in the liver and
secreted through the bile - glucuronic acid/sulfate is cleaved off by
bacteria in GI tract - drug is reabsorbed & excreted through urine -
directly excreted in colon.
Excretion

46. Exhale air:
Gases and volatile liquid- eliminate through lung, irrespective
of their lipid solubility. Ex- general anesthetics, alcohol etc.
Milk:
Most of the lipid soluble and less protein bound drugs cross
better into the breast milk. Milk has lower pH (7) than plasma
thus basic drug concentrated more in it. However the total
amount of drug excrete through breast milk is very minute
quantity, thus causing without any ill effect to the suckling
infant.
Routes of drug excretion

47. Drugs are eliminated from the body primarily by the kidneys.
The following 3 mechanisms are involved in the excretion of
drugs :
1. Glomerular Filtration :
It's an passive process. Only free drugs can pass through the
glomerululs. Glomerular capillaries alllow drug molecule of
<20000MW to diffuse into glomerular filtrate.
Molecular size,charge & shape of molecules influence the
glomerular filtration. Lipid solubility & pH don't influence the
passage of drugs into the glomerular filtrate.
Avg GFR in healthy individual is 120 ml/min.
Renal excretion

48. 2. Tubular secretion :
Many drugs which don't enter into glomerular filtration, they
undergo tubular secretion which mainly occurs in proximal
tubules. The cells of proximal tubule actively transport drugs
from the plasma into the lumen of the tubule.
It's an active process. So the process require a carried & energy
for transportation of molecules against conc. gradient.
Renal excretion

49. 3. Tubular reabsorption :
Tubular epithelium has the properties of a lipid membrane. So drugs
filtered in glomerulas are reabdorbed & diffuses back into the plasma.
More than 90% of glomerular filtrate is reabsorbed.
Reabsorption results in increase in the half life of the drug. Reabsorption
is particularly important for endogenous substances like
glucose,AA,vitamins.
It depends on -
1) Lipid solubility :
a) Lipid soluble drug filtered at glomerulus & 99% diffuse back into the
plasma.
b) But the liquid insoluble drugs cannot be reabsorbed.
2) Ionization of drug is at the urinary pH :
a) Weak base ionize more in acidic media and less reabsorbed.
b) Weak acid more ionize in alkaline media and are less reabsorbed
Renal excretion

50. Renal excretion

51. ▪ Clearance : Clearance of a drug is the theoretical value of
Plasma from which drug is totally removed per unit time .
It's the ratio of rate of elimination rate of elimination to the
conc of drug in plasma. Cl = Rate of elimination/Plasma
conc.
For instance of a drug has 20 mcg/ml conc & rate of elimination
is 100 mcg/min., then Cl = 100/20 = 5mil/min.
▪ Plasma half life : Defined as the time required to reduce the
plasma concentration by 50% in the body.
T 1/2 = ln2/k [k=elimination rate constant= Cl/V]
So, T 1/2 = ln2×V/ Cl
Kinetics of elimination

52. ▪ First order kinetics : The rate of elimination is directly
proportional to drug conc.
It follows the Law of mass action.
Plasma half life remains constant.
Clearance remains constant.
Ex : Low dose aspirin
▪ Second order kinetics : The rate of elimination remains
constant irrespective of drug concentration.
It doesn't follows the law of mass action .
Plasma half life varies with the rate of elimination .
Clearance decreases with increase in concentration .
Ex : High dose aspirin.
Kinetics of elimination

53. ▪ Loading dose :
A single or few repeated or series of doses that may be given at the very
beginning of the therapy to reach the desire plasma concentration
rapidly.
LD= Target Cp x V / Fraction of dose(F)
Thus, loading dose govern by V and fraction of dose. Plasma clearance
(CL) or plasma half life do not have any influence on Loading dose.
▪ Maintenance Dose:
It is the amount of drug require to give in each intervals to replace the
drug eliminated at that particular interval since the preceding dose
require to maintain a steady state of drug always in the body.
Maintenance dose = dosing rate x dosing interval
Dosing rate = Target Cp x CL.
Kinetics of elimination