Pharmacokinetics (PK) is the branch of pharmacology dedicated to determining the fate of substances administered to a living organism. It is concerned with the absorption, distribution, metabolism, and excretion (ADME) of drugs. Understanding pharmacokinetics is critical in drug development, therapeutic drug monitoring, and individualized patient care. This paper delves into the fundamental aspects of pharmacokinetics, examining each stage of a drug's journey through the body and its implications for drug efficacy and safety. Absorption Definition and Importance Absorption refers to the process by which a drug enters the bloodstream from its site of administration. The rate and extent of absorption determine the drug's bioavailability, which influences therapeutic effectiveness. Factors Affecting Absorption Route of Administration: Oral, intravenous (IV), intramuscular (IM), subcutaneous, rectal, and transdermal routes each have unique absorption characteristics. IV administration provides 100% bioavailability. Physicochemical Properties: Solubility, molecular size, ionization, and lipophilicity affect a drug’s ability to cross biological membranes. Gastrointestinal (GI) Environment: pH levels, gastric emptying time, and the presence of food or other drugs influence oral drug absorption. Drug Formulation: Immediate-release vs. controlled-release formulations affect how quickly and efficiently a drug is absorbed. Bioavailability Bioavailability is a key pharmacokinetic parameter indicating the fraction of an administered dose that reaches systemic circulation in an active form. It is particularly significant for orally administered drugs, which must pass through the liver (first-pass metabolism) before reaching circulation. Distribution Definition Distribution is the reversible transfer of a drug from the bloodstream to various tissues and organs. Volume of Distribution (Vd) Volume of distribution is a theoretical value that relates the amount of drug in the body to the concentration in plasma. A high Vd indicates extensive distribution into tissues, while a low Vd suggests confinement to the vascular compartment. Factors Influencing Distribution Blood Flow: Organs with high perfusion (e.g., liver, kidneys, brain) receive drugs faster. Plasma Protein Binding: Drugs may bind to proteins like albumin, affecting free (active) drug concentration. Tissue Binding: Some drugs accumulate in specific tissues (e.g., fat, bone), impacting duration of action. Membrane Permeability: The blood-brain barrier and placental barrier restrict drug entry into certain compartments. Special Considerations Redistribution: Lipophilic drugs may initially act in high-perfusion organs but later redistribute to fat stores, reducing efficacy. Barriers: Drug distribution can be limited by barriers like the blood-brain barrier (BBB), which protects the CNS. Metabolism Definition Metabolism is the biotransformation of drugs into more water-soluble compounds

1. Pharmacokinetics
(Absorption & Distribution)

2. OUTLINE
• Modes of permeation and transport
• Bioavailability
• First pass metabolism
• Equivalence
• Redistribution
• Plasma protein binding
• Volume of distribution

4. PHARMACOKINETICS
• It is the effect of body on the drug i.e. movement of the drug in,
through and out of the body.
• Pharmacokinetics is also called ADME study as it deals with
Absorption, Distribution, Metabolism and Excretion of a drug.

6. ABSORPTION

7. Absorption
• Only lipid soluble drugs can cross the biological membranes.
• If a drug is a weak electrolyte, it is the unionized form which is lipid soluble and the ionized form
is water soluble.
• When medium is same, drugs can cross the membrane.
• Acidic drugs can cross the membranes in acidic medium i.e. acidic drugs are lipid soluble in
acidic medium.
• Opposite is also true for basic drugs.

8. Weak Acids Weak Bases
Barbiturates e.g. phenobarbitone Morphine
NSAIDs e.g. aspirin, diclofenac Atropine
Methotrexate Amphetamines
Sulfonamides Quinine
Penicillins Hyoscine

9. • There is never 100% lipid solubility or water solubility, because ionization of a
drug is never 100% or 0%.
• If pH of the medium is equal to pKa, then drug is 50% ionized and 50% un-
ionized.
• If the pH of the medium is more than pKa (medium becomes alkaline).
– For acidic drugs, ionized form increases and non-ionized form decreases.
– For basic drugs, un-ionized form increases and ionized form decreases
• If the pH of the medium is less than pKa, opposite happens, i.e. acidic drugs will
be in more un-ionized form and basic drugs be more ionized.

10. • This ionized or unionized fraction depends on difference (d) between
pH and pKa.
• When pH = pKa (d = 0) Ionization is 50% and unionized fraction is
also 50%.
• When pH – pKa = 1 (d = 1) one form is 90% and other form is 10%.
• D=2, one form is 99% and other form is 1%.

11. Henderson-Hasselbach equation
The ratio of nonionized to ionized drug at any pH may be calculated
from the Henderson-Hasselbach equation:

12. Ion trapping
• 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. This phenomenon, known as ion trapping.
• It is an important process in drug distribution with potential therapeutic benefit.
• Alkaline urine favors excretion of weak acids; acid urine favors excretion of weak
bases.
• Elevation of urine pH (by giving sodium bicarbonate) will promote urinary excretion of
weak acids such as aspirin (pKa ~ 3.5) and urate (pKa ~ 5.8).

13. Lipinski rule of FIVE
• Molecular weight should be less than 500 daltons.
• Log P value should be less than 5
• Hydrogen bond donors should be less than 5
• Hydrogen bond acceptors should be less than 10

14. Factors affecting absorption
• Aqueous solubility
• Concentration
• Area of absorbing surface (*Why aspirin is primarily absorbed from small intestine although pH of
intestine is between 6 & 8 ? )
• Vascularity of the absorbing surface
• Route of administration
• Gastric emptying & gut motility
• Particle size & formulation (Why particle size of drug in solid form is important in case of certain
drugs like aspirin ?)
• Presence of food & other substance

15. Bioavailability
• It is the fraction of administered drug that reaches the systemic circulation in the unchanged form.
• Some of the drug may be metabolized (first pass metabolism or pre-systemic metabolism) and rest
of the drug reaches the systemic circulation.
• Absorption and first pass metabolism are two important determinants of bioavailability.
• By i.v. route, bioavailability is 100%.
* Why bioavailability of tetracyclines decreases when taken with milk?

16. Bioavailability can be calculated by comparing the AUC
(area under plasma concentration time curve) for i.v. route
and for that particular route.
AUC tells about the extent of absorption of the drug.

18. Bioequivalence
• Many different pharmaceutical companies can manufacture same
compound (with same dose as well as dosage form) e.g. phenytoin is
available as tab. Dilantin as well as Tab. Eptoin.
• If the difference in the bioavailability of these two preparations (same
drugs, same dose, same dosage forms) is less than 20%, these are
known to be bioequivalent.

19. • Chemical equivalence: If two or more dosage forms of a drug contain
the same amount of drug.
• Therapeutic equivalence: If two different drugs produce the same
therapeutic or clinical response.
• Clinical equivalence: Response produced by two or more brand of a
generic drug is same.

20. DISTRIBUTION

21. Distribution of blood flow in 70 Kg Male at rest

22. Volume of Distribution

23. • After the drug reaches the blood, it may be distributed to various tissues. This is determined by a
hypothetical parameter, Volume of distribution (Vd).
• Apparent volume of distribution which can be defined as “the volume that would accommodate all
the drug in the body, if the concentration throughout was the same as in plasma”.
• If more amount of drug is entering the tissues, it has a higher volume of distribution and vice-a-
versa.
• Higher dose has to be administered to attain the same plasma concentration for drugs having high
Vd than those having low Vd. This high dose is called loading dose.
• Vd is the main determinant of loading dose. Chloroquine is the drug with highest Vd (1300 L).

25. Redistribution
• Highly lipid-soluble drugs get initially distributed to organs with high blood flow, i.e. brain, heart,
kidney, etc.
• Later, less vascular but more bulky tissues (muscle, fat) take up the drug—plasma concentration falls
and the drug is withdrawn from the highly perfused sites.
• If the site of action of the drug was in one of the highly perfused organs, redistribution results in
termination of drug action.
• Greater the lipid solubility of the drug, faster is its redistribution (propofol, diazepam).
*Anaesthetic action of thiopentone sod. Injected i.v. is terminated in few minutes due to redistribution.

26. Passage of drugs across capillaries

27. Passage across placenta
• Placental membranes are lipoidal and allow free passage of lipophilic drugs but not hydrophilic.
• The placental efflux P-gp and other transporters like BCRP, MRP3 also serve to limit fetal
exposure to maternally administered drugs.
• Placenta is a site for drug metabolism as well, which may lower/modify exposure of the fetus to
the administered drug.
• Some influx transporters also operate at the placenta.
* why a newborn is more susceptible to many drugs ?

28. Plasma protein binding
• Acidic drugs generally bind to plasma albumin and basic drugs to α1 acid
glycoprotein.
Clinically significant implications of plasma protein binding are:
(i) Highly plasma protein bound drugs are largely restricted to the vascular
compartment.
(ii) The bound fraction is not available for action.
(iii) High degree of protein binding generally makes the drug long acting, because
bound fraction is not available for metabolism or excretion.

29. (v) One drug can bind to many sites on the albumin molecule. Conversely, more
than one drug can bind to the same site. This can give rise to displacement
interactions among drugs bound to the same site.
Clinically important displacement interactions are:
• Aspirin displaces sulfonylureas.
• Indomethacin, phenytoin displace warfarin.
• Sulfonamides and vit K displace bilirubin (kernicterus in neonates).
• Aspirin displaces methotrexate.

30. • Two highly bound drugs do not necessarily displace each other—their binding
sites may not overlap, e.g. probenecid and indomethacin are highly bound to
albumin but do not displace each other. Similarly, acidic drugs do not generally
displace basic drugs and vice versa.
• Tissue storage: Tetracyclines on bone and teeth, chloroquine on retina,
streptomycin on vestibular apparatus, emetine on heart and skeletal muscle.
• Drugs with low Vd are restricted to the vascular compartment and their poisoning
can be benefitted by dialysis.

31. Drugs with high plasma protein binding
• Warfarin
• Verapamil
• Imipramine
• Fluoxetine
• Cyclosporine
• Tolbutamide
• Chlorpropamide
• Benzodiazepines (Diazepam, Midazolam)

32. Albumin bound drugs
• Diclofenac
• Ibuprofen
• Glimepiride
• Aripiprazole
• Diazepam
Alpha 1 acid glycoprotein
• Imipramine
• Alpha blockers
• Lignocaine
• Quinidine

33. Clinical importance of plasma protein binding
• Duration of action: Drugs with high PPB are usually long acting.
• Distribution: High PPB drugs will stay in plasma, thus have low Vd.
• Displacement: High PPB drugs can be displaced by another highly PPB drug.
• Dialysis: It is not effective for drugs having high PPB.

34. Dialysis in drug poisoning
• Dialysis does not filter proteins. Therefore, drugs having high plasma protein
binding (e.g. diazepam) cannot be removed by dialysis.
• Dialysis removes only those drugs which are present in sufficient free
concentration in plasma. Thus, drugs having high volume of distribution [More in
tissues but less in Plasma] are difficult to be removed by dialysis e.g. digoxin,
propranolol etc.
• Thus, drugs having low Vd and low PPB are good candidates of dialysis e.g.
salicylates.

35. Dialysis is not effective in poisoning
• A: Amphetamines
• V: Verapamil
• O: Organophosphates and opioids
• I: Imipramine
• D: Digitalis
• Dialysis: Diazepam

36. THANK YOU