The document discusses the dynamics of drug absorption and distribution. It describes how physicochemical factors like molecular size, ionization, and lipid solubility determine how drugs pass through membranes. Drugs can cross cell membranes through passive diffusion, facilitated transport, or active transport. Absorption involves drugs crossing membranes and entering blood circulation, which depends on factors like solubility, molecular size, and dosage form. Distribution involves drugs spreading throughout tissues, influenced by blood flow, protein binding, and access to different compartments like the brain or placenta.

1. The dynamics of drug absorption and
distribution
Presented by : Tailor Himani Rajubhai
Department of Pharmacology
L. M. College Of Pharmacy

2. Physicochemical factors in transfer of drugs
across membranes:
• The determining characteristics of the drug are
its molecular size and shape, degree of
ionization, relative lipid solubility of its ionized
and unionized forms, and its binding to tissue
proteins.
• Despite of structural differences the diffusion
and transport of drugs across these various
boundaries have many common characteristics,
since drugs in general pass through cells rather
than between them. The plasma membrane
thus represents the common barrier.
• Drug molecules can cross cell membrane by:
passive diffusion; protein-mediated transport (
facilitated and active transport)

3. Biological Membrane
• Bilayer of amphipathic lipid
 hydrocarbon chains oriented
inward to form a continues
hydrophilic tail and hydrophilic
head oriented outward.
• Membrane proteins embedded
in the bilayer serve as receptors,
ion channel or transporters to
elicit electrical or chemical
signaling pathways and provide
selective targets for drug action.
-

4. Passage of drug across cell membrane
• The cell membrane acts as a biological barrier. The following are the
processes by which a drug can cross biological membrane
1. Passive transport
-Diffusion(simple)
-Filtration
-osmosis
2. Specialized transport
-Active transport
*Primary active transport(direct active transport)
*secondary active transport(co-transport)

5. -Endocytosis
*Phagocytosis
*pinocytosis
*Receptor mediated endocytosis

6. A. Passive membrane transport
• This transport is energy independent and no utilization of ATPs.
a. Diffusion (simple)
• Diffusion is the net movement of drug molecules from an area of high concentration to an area with lower
concentration.
• The difference of concentration between the two areas is termed as the concentration gradient, and
diffusion will continue until this gradient has been eliminated.
• Diffusion across the cell membrane depends on concentration gradient and lipid solubility. Lipid solubility
depends on ionization. Un-ionized drugs are more lipid soluble and are better absorbed (more reabsorbed
in the kidneys and less excreted).
• Ionized drugs are less lipid soluble and are less absorbed (less reabsorbed in kidneys and more excreted).
Ionization depends on pH of drug and pH of the medium (surrounding fluid).
• If the pH is the same the drug remain unionized and become more lipid soluble and absorbed better. Acidic
drugs like aspirin, barbiturates, etc. are better absorbed from the stomach. Alkaline drugs like morphine,
atropine, and chloroquine are better absorbed from the small intestine. If pH is opposite-> drug is ionized->
less lipid soluble-> less absorption (e.g. alkaline drugs are poorly absorbed in the stomach). .

7. b. Filtration and Osmosis
• This can be accelerated if hydrodynamic flow of the solvent is
occurring under hydrostatic or osmotic pressure gradient. E.g: across
most capillaries including glomeruli.
Filtration- is movement of drugs through aqueous pores in the
membrane or through paracellular spaces.
• Lipid insoluble drugs can cross the biological membrane by filtration if
the molecular size is smaller than that of the diameter of pores.
Osmosis-Osmosis is the movement of water molecule through the cell
membrane (semi permeable membrane) from the region of higher
water concentration to the region of less water concentration is called
osmosis

9. Weak electrolytes and influence of pH
• Most drugs are- weak acids or bases.
• Non-ionized molecules- lipid soluble- diffuse across membrane.
• Transmembrane distribution of weak electrolyte is usually
determined by its pKa and pH gradient. pKa is numerically equal to
the pH at which the drug is 50% ionized.
• Henderson- hasselbalch equation: for weak acid,
• pH= pKa+ log [A-]/ [HA] where, A- is ionized and HA is unionized drug.
If concentration of both is equal then log 1= 0 hence pH= pKa.
• If pH is increased by scale 1 scale then log [A-]/ [HA] =1 or [A-]/ [HA]
=10. Similarly if reduced by 1 then [A-]/ [HA] = 1/10.

10. B. Specialized transport

11. a. Facilitated diffusion(solute carrier SLC transporters)-It is the movement
of drug molecules across the cell membrane via special transport proteins
that are present within the cellular membrane.
• Many large molecules, such as glucose, are insoluble in lipids and too large
to pass through the membrane pores. Therefore, it will bind with its specific
carrier proteins, and moved through the cellular membrane.

12. • Active transport- In active transport, the drug molecule penetrates in
the lipid bilayer membrane from lower concentration to the higher
concentration of solutes against the concentration gradient by utilizing
energy (ATP) and with the help of carrier proteins.
• There are two types
- Primary active transport and
-secondary active transport.

13. C . Endocytosis

14. Absorption
• Absorption is the movement or transfer of a drug from it’s site of
application into the blood circulation.
• Not only the fraction of administered dose that gets absorbed, but also the
rate of absorption is important
• When a drug is administered intravenously, absorption is not required
because the drug is transferred from the administration device directly
into the bloodstream. In the case of intravenous administration, the entire
dose of the drug is available to move to the sites of drug action.
• Drug administration by other routes may result in only partial absorption
and thus, lower bioavailability.
• Passage of drug across cell membrane- The cell membrane acts as a
biological barrier.

15. Factors affecting absorption
1. Lipid solubility- Absorption of drugs depends on lipid solubility.
Absorption is more if the drug is lipid soluble. Lipid solubility depends
on ionization. Un-ionized drugs are more lipid soluble and are better
absorbed. Ionized drugs are less lipid soluble and are less absorbed.
2. Molecular size- Smaller the molecular size of the drug rapid is the
absorption.
3. Particle size - Particle may be composed either of a single molecule
or more than hundred molecules. Larger is the particle size, slower will
be the diffusion and absorption and vice versa.

16. 4. Degree of ionization- Un-ionized drugs are more lipid soluble and
are better absorbed (more reabsorbed in the kidneys and less
excreted). Ionized drugs are less lipid soluble and are less absorbed
(less reabsorbed in kidneys and more excreted). Ionization depends on
pH of drug and pH of the medium (surrounding fluid). If the pH is the
same the drug remain unionized and become lipid soluble and
absorbed better. (e.g. acidic drugs like aspirin, barbiturates, etc. are
better absorbed from the stomach. Weakly alkaline drugs like
morphine, atropine, chloroquine are better absorbed from the small
intestine.
5. Physical forms- Drugs may exist as solids, liquids or gases. Gases are
rapidly absorbed than the liquids, while liquids are rapidly absorbed
than the solids. Thus the drugs in syrup or suspension form are rapidly
absorbed than the tablets or capsules. Volatile general anaesthetics
absorbed rapidly through the pulmonary route.
.

17. 6. Chemical nature-Chemical nature is responsible for the selection of the
route of drug administration. Examples- Heparin is a drug with large
molecular weight, and is cannot be given orally, insulin is degraded if given
orally, benzyl penicillin also get degraded if given orally. Hence these drugs
should be administered parenterally to avoid the inactivation
7. Dosage forms- Dosage forms affect the rate and extent of absorption.
Example – nitroglycerin when given by sublingual route disintegrates rapidly
but stays for a shorter duration. When it is given orally, it disintegrates slowly
and stays for longer duration.
8. Concentration - If the drug concentration increases the drug absorption
across the cell membrane also increases.
9. Area of absorptive surface- Most of the drugs are given orally because of
the large area of absorptive surface, so that greater absorption occurs.
Organophosphate compounds (insecticides) are highly lipid soluble and
poisoning can occur even by absorption through skin.

18. 10.Vascularity - If the vascularity (blood supply) is more, the drug absorption
also increases. In shock, the blood supply decreases, hence the drug
absorption decreases. During IM inj massage increases vascular supply and
drug absorption
11. pH – Acidic pH favours the absorption of acidic drugs and basic pH
favours the absorption of basic drugs.
12. Presence of other substances- Food can increase or decrease the drug
absorption. Examples- Atorvastatin is better absorbed when taken with the
food. Milk decreases the absorption of iron. Vitamin C enhances the
absorption of iron. Milk decreases the absorption of tetracycline.
13. GI motility- The drug absorption gets altered in diarrhoea or
constipation.
14-Diseases- In diarrhoea drug absorption decreases, malabsorptive
syndrome- decreases drug absorption, in achlorhydria – decreases the
absorption of acidic drugs.

19. DRUG DISTRIBUTION
• Once in the blood, drugs are simultaneously distributed throughout
the body and eliminated. Typically, distribution is much more rapid
than elimination, is accomplished via the circulation, and is influenced
by regional blood flow.
Volume of Distribution (Vd)
Definition: Apparent Volume of distribution is defined as the volume
that would accommodate all the drugs in the body, if the concentration
was the same as in plasma,
Expressed as: in Liters
Vd =
Dose administered IV
Plasma concentration

20. A. Compartments
1. Central Compartment
• The central compartment includes the well-perfused organs and
tissues
• (heart, blood, liver, brain and kidney) with which drug equilibrates
rapidly.

21. 2. Peripheral Compartment(s)
• The peripheral compartment(s) include(s) those organs (e.g., adipose
and skeletal muscle) which are less well-perfused, and with which
drug therefore equilibrates more slowly.
• Redistribution from one compartment to another often alters the
duration of effect at the target tissue.
• For example, thiopental, a highly lipid-soluble drug, induces
anaesthesia within seconds because of rapid equilibration between
blood and brain.
• Despite the fact that the drug is slowly metabolized, however, the
duration of anesthesia is short because of drug redistribution into
adipose tissue, which can act as a storage site, or drug reservoir.

22. 3. Special compartment
• Several special compartments deserve mention.
• Entry of drug into the cerebrospinal fluid (CSF) and central nervous
system (CNS) is restricted by the structure of the capillaries and
pericapillary glial cells (the choroid plexus is an exception).
• The blood-brain barrier limits the success of antibiotics, anticancer
drugs and other agents used to treat CNS diseases.
• Drugs also have relatively poor access to pericardial fluid, bronchial
secretions and fluid in the middle ear, thus making the treatment of
infections in these regions difficult.

24. B. Protein Binding
• Many drugs bind to plasma proteins.
Weak acids and neutral drugs bind particularly to albumin,
while basic drugs tend to bind to alpha-1-acid glycoprotein
(orosomucoid).

25. Effects on drug distribution
• Only that fraction of the plasma drug concentration which is freely
circulating (i.e., unbound) can penetrate cell membranes.
• Protein binding thus decreases the net transfer of drug across
membranes.
• Drug binding to plasma proteins is generally weak and rapidly
reversible, however, so that protein-bound drug can be considered to
be in a temporary storage compartment.
• The protein concentration of extravascular fluids (e.g., CSF, lymph,
synovial fluid) is very low.
• The extent of protein binding must be considered in interpreting
"blood levels" of drugs.

26. Placental Transfer of Drugs
• The transfer of drugs across the placenta is of critical importance
because drugs may cause anomalies in the developing fetus.
• Administered immediately before delivery, as is often the case with
the use of tocolytics in the treatment of preterm labor, they also may
have adverse effects on the neonate.
• As in the brain, P-gp and other export transporters are present in the
placenta and function to limit fetal exposure to potentially toxic
agents.

27. References:
• http://downloads.lww.com/wolterskluwer_vitalstream_com/sample-
content/9780781773485_Sakai/samples/Sakai_Ch03.pdf
• “The pharmacological basis of therapeutics “by Goodman & Gilman,
tenth edition.
• “Essential of medical pharmacology” by KD Tripathi, seventh edition.

28. •THANK YOU