BAHAN AJAR UNTUK TOPIK MINGGU KE-1

Drug Distribution
MATA KULIAH :

FARMAKOKINETIKA

Disusun oleh PJMK :

M.M. Farida Lanawati Darsono, S.Si.,M.Sc

Semester Genap
Tahun Akademik : 2021-2022

Universitas Katolik Widya Mandala Surabaya

Fakultas Farmasi

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 Topic 1: Drug Distribution
point
• To understand and describe the process by which drugs are distributed throughout the
body
• To understand the effect of protein binding on drug distributed

drug distribution patterns: 4 types

• The drug may remain largely within the vascular system
(ex: dextran ~plasma/drugs which stronglybound tp plasma)
• Some low molecular weight water soluble compounds
(become uniformly distributed throughout the body water) - (ex: ethanol / a few sulfonamide)
• A few drugs are concentrated specifically in one or more tissues that may or may not be the
site of action
(ex:iodine~thyroid glands/chloroquine~liver 1000x than present in plasma/tetracycline
~irreversible bound to bone & developing teeth )
• Most drugs exhibit a non-unifrorm distribution in the body with variations that are largely
determined by the ability to pass through membranes and their lipid/water solubility
(ex: the highest concentrations are often present in the : kidney, liver, intestine)

Nb:
• pattern 4 is the most common being a combination of patterns 1,2 and 3
• Distribution of various substances within the body is NOT HOMOGENOUS

definition : distribution
• Distribution: Movement of drug from the central compartment (blood) to peripheral
compartments (tissues) where the drug is present.
• Distribution of a drug from systemic circulation to tissues is dependent on lipid solubility ,
ionization, molecular size , binding to plasma proteins , rate of blood flow and special
barriers
• The body compartments include extracellular (plasma, interstitial) and intracellular which are
separated by capillary wall and cell membrane
• Distribution: the passage of drugs from blood to tissues.

Distribution ---- where do drugs go?

Once a drug has gained excess to the blood stream, the drug is subjected to a number of
processes called as Disposition Processes that tend to lower the plasma concentration.
1. Distribution which involves reversible transfer of a drug between compartments.
2. Elimination which involves irreversible loss of drug from the body. It comprises of
biotransformation and excretion.

Diffusion and hydrostatic pressure

a. Passive diffusion : gradient conc --- fick’s law
b. Hydrostatic pressure :
(*) a pressure gradient between the arterial and of the capillaries entering the tissue and the
venous capillaries leaving the tissue
(*) resonsible for penetration of water soluble drugs into spaces, between endothelial celss
& possible into lymph

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The important factors in dtermining the rate of drug diffusion are :
 The membranes thickness
 Diffusion coefficient of the drugs
 Concentration gradient across the capillaries membranes

Factor affecting drug distribution

a. Rate of distribution :
 membranes permeability
 blood perfussion
b. Extent of distribution
 lipid solubility
 pH – pka
 plasma protein binding
 intracellular binding
c. Tissue size
d. Tissue storage

Rate limiting of distribution (tahap penetu kecepatan distribusi)

a. Drug --- diffuse rapidly -----blood flow : perfussion rate limited (flow limited)
b. Drug --- slow diffusion -----membrane cell : permeability rate limited (diffusion)

Redistribution
 Highly lipid soluble drugs when given by i.v. or by inhalation initially get distributed to
organs with high blood flow, e.g. brain, heart, kidney etc.
 Later, less vascular but more bulky tissues (muscles,fat) take up the drug and plasma
concentration falls and 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.
 Greater the lipid solubility of the drug, faster is its redistribution.

Dose
Vd 
Plasma concentration
Volume of Distribution
• Volume of Distribution (Vd) [ml or l]:
= Amount of drug in the body [mg] / drug concentration plasma [mg/ml]
• Volume of Distribution (Vd): apparent volume of body water that drug appears to distribute
into to produce a drug concentration equal to that in the blood.
• Apparent and hypothetical volume in which the drug is dispersed.
• Vd is an apparent volume (volume that the drug must be distributed in to produce measured
plasma concentration
• Drug with near complete restriction to plasma compartment would have Vd = plasma
volume (.04 L/kg) = 2.8 L/70 kg patient
• But: Many drugs are highly tissue bound => large Vd
e.g. Chloroquine: Vd = 13,000 L

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Distribution
• Membrane permeability
– cross membranes to site of action
• Plasma protein binding
– bound drugs do not cross membranes
– malnutrition = albumin =  free drug
• Lipophilicity of drug
– lipophilic drugs accumulate in adipose tissue
• Volume of distribution

Factors affecting the equilibrium distribution of drugs across the compartments

1. Membrane-impermeant drugs will be excluded from the intracellular volume (Example:
Lithium)
2. Lipophilic drugs will be enriched in the fat tissue (example: Thiopental – see later)
3. Drugs with a high degree of protein binding will be more concentrated in the plasma (the
intravascular volume) than in the interstitial fluid
• To be absorbed and distributed, drugs must cross barriers (membranes) to enter and leave the
blood stream.

Body contains two type of barriers which are made up of epithelial or endothelial cells:
A. External (Absorption Barriers):
Keratinized epithelium (skin), ciliated epithelium (lung), epithelium with microvilli
(intestine)
These epithelial cells are connected via zonulae occludens (tight junctions) to create an
unbroken phospholipid bilayer.
Therefore, drugs MUST cross the lipophilic membrane to enter the body (except
parenteral)

B. Internal (Blood-Tissue Barriers):

Drug permeation occurs mostly in the capillary bed, which is made up of endothelial cells
joined via zonulae occludens.
Blood-Tissue Barrier is developed differently in various capillary beds:
1. Cardiac muscle: high endo- and transcytotic activity-> drug transport via vesicles
2. Endocrine glands, gut: Fenestrations of endothelial cells (=pores closed by diaphragms)
allow for the passage of small molecules.
3. Liver: Large fenestration (100 nm) without diaphragms-> drugs exchange freely
between blood and interstitium
4. CNS, placenta: Endothelia lack pores and possess only little trans-cytotic activity->
drugs must diffuse transcellularly, which requires specific physicochemical properties
-> Barriers are very restrictive, permeable only to certain types of drugs.

• Plasma: 4 liters.
• Interstitial volume: 10 liters.
• Intracelullar volume: 28 liters
• Plasma compartment
(*) Vd: around 5 L.
(*) Very high molecular weight drugs, ordrugs that bind
to plasma proteins excesively
Example: heparin 4L (3-5)

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 • Extracellular fluid
(*) Vd: between 4 and 14 L.
(*) Drugs that have a low molecular weight but are hydrophilic.
Example : Atracuronium 11 L (8-15)

Vd equal or higher than total body water

• Diffusion to intracelullar fluid . Vd equal to total body water.

– Ethanol 38 L (34-41)
– Alfentanyl 56 L (35-77)
• Drug that binds strongly to tissues. Vd higher than total body water.
– Fentanyl: 280 L
– Propofol: 560 L
– Digoxin:385 L

Key factor in the onset of drug action-Body Water Compartments

 BODY WATER COMPARTMENTS: 50Kg & 100Kg ---- (110 lb) (220 lb)
 Total body water (60% body weight) = 0.6 L/Kg, 30 L & 60 L
 Extracellular (20% body weight) = 0.2L/Kg, 10 L & 20 L
 Plasma (4% body weight) = 0.04L/Kg, 2 L & 4 L
 Interstitial (16% body weight) = 0.16L/Kg, 8 L & 16 L
 Intracellular (40% body weight) = 0.4 L/Kg, 20 L & 40 L
 Drugs which bind selectively to Plasma proteins e.g. Warfarin have Apparent volume of
distribution smaller than their Real volume of distribution.
 The Vd of such drugs lies between blood volume and total body water i.e. b/w 6 to 42 liters.
 Drugs which bind selectively to Extravascular Tissues e.g. Chloroquine have Apparent
volume of distribution larger than their Real volume of distribution.
 The Vd of such drugs is always greater than 42 liters.

Body fluids
 water sources (water drinking/water contained in food/metabolism to CO 2 & H2O)
 water losses (urinary loss, fecal loss, insensible H2O loss, sweat loss, pathological loss)
 electrolytes (electrolyte losses: renal excretion, stol losses, sweating, abnormal routes
(vomit & diarrhea)

Differences In Drug Distribution Among Various Tissues Arises Due To a Number of

Factors:
Tissue Permeability of the Drug
a. Physiochemical Properties of the drug like Molecular size, pKa and o/w Partition
coefficient.
b. Physiological Barriers to Diffusion of Drugs.
Organ / Tissue Size and Perfusion Rate
Binding of Drugs to Tissue Components (Blood components, Extravascular Tissue Proteins)
Miscellaneous Factors (Age, Pregnancy, Obesity, Diet, Disease states, and Drug Interactions)

 Tissue Permeability of the Drugs depend upon:

1. Rate of Tissue Permeability, and
2. Rate of Blood Perfusion.

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 The Rate of Tissue Permeability, depends upon Physiochemical Properties of the drug as
well as Physiological Barriers that restrict the diffusion of drug into tissues.
 Physiochemical Properties that influence drug distribution are:
i. Molecular size,
ii. pKa, and
iii. o/w Partition coefficient.

 Drugs having molecular wt. less than 400 daltons easily cross the Capillary Membrane to
diffuse into the Extracellular Interstitial Fluids.
 Now, the penetration of drug from the Extracellular fluid (ECF) is a function of :-
 Molecular Size:
Small ions of size < 50 daltons enter the cell through Aq. filled channels where as larger size
ions are restricted unless a specialized transport system exists for them.
 Ionisation:
A drug that remains unionized at pH values of blood and ECF can permeate the cells more
rapidly.
Blood and ECF pH normally remains constant at 7.4, unless altered in conditions like
Systemic alkalosis/acidosis.

PENETRATION OF DRUGS THROUGH BLOOD BRAIN BARRIER

• A stealth of endothelial cells lining the capillaries.
• It has tight junctions and lack large intra cellular pores.
• Further, neural tissue covers the capillaries.
• Together , they constitute the BLOOD BRAIN BARRIER.
• Astrocytes : Special cells / elements of supporting tissue are found at the base of endothelial
membrane.
• The blood-brain barrier (BBB) is a separation of circulating blood and cerebrospinal fluid
(CSF) maintained by the choroid plexus in the central nervous system (CNS).

Since BBB is a lipoidal barrier

 It allows only the drugs having high o/w partition coefficient to diffuse passively
where as moderately lipid soluble and partially ionized molecules penetrate at a slow rate.
 Endothelial cells restrict the diffusion of microscopic objects (e.g. bacteria ) and large or
hydrophillic molecules into the CSF, while allowing the diffusion of small hydrophobic
molecules (O2, CO2, hormones).
 Cells of the barrier actively transport metabolic products such as glucose across the barrier
with specific proteins.

Various approaches to promote crossing BBB:

• Use of Permeation enhancers such as Dimethyl Sulfoxide.
• Osmotic disruption of the BBB by infusing internal carotid artery with Mannitol.
• Use of Dihydropyridine Redox system as drug carriers to the brain ( the lipid soluble
dihydropyridine is linked as a carrier to the polar drug to form a prodrug that rapidly crosses
the BBB )

PENETRATION OF DRUGS THROUGH PLACENTAL BARRIER

• Placenta is the membrane separating Fetal blood from the Maternal blood.
• It is made up of Fetal Trophoblast Basement Membrane and the Endothelium.
• Mean thickness in early pregnancy is (25 µ) which reduces to (2 µ) at full term.

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• Many drugs having mol. wt. < 1000 Daltons and moderate to high lipid solubility e.g.
ethanol, sulfonamides, barbiturates, steroids, anticonvulsants and some antibiotics cross the
barrier by simple diffusion quite rapidly .
• Nutrients essential for fetal growth are transported by carrier mediated processes.

Blood – Cerebrospinal Fluid Barrier:

 The Cerebrospinal Fluid (CSF) is formed mainly by the Choroid Plexus of lateral, third and
fourth ventricles.
 The choroidal cells are joined to each other by tight junctions forming the Blood – CSF
barrier which has permeability characteristics similar to that of BBB.
 Only high lipid soluble drugs can cross the Blood – CSF barrier.

Blood – Testis Barrier:

 It has tight junctions between the neighboring cells of sertoli which restricts the passage of
drugs to spermatocytes and spermatids.

Organ / Tissue Size and Perfusion Rate

 Perfusion Rate is defined as the volume of blood that flows per unit time per unit volume of
the tissue.
 Greater the blood flow, faster the distribution.
 Highly perfused tissues such as lungs, kidneys, liver, heart and brain are rapidly equilibrated
with lipid soluble drugs.
 The extent to which a drug is distributed in a particular tissue or organ depends upon the size
of the tissue i.e. tissue volume.

Miscellaneous Factors
 Diet: A Diet high in fats will increase the free fatty acid levels in circulation thereby
affecting binding of acidic drugs such as NSAIDS to Albumin.
 Obesity: In Obese persons, high adipose tissue content can take up a large fraction of
lipophilic drugs.
 Pregnancy: During pregnancy the growth of the uterus, placenta and fetus increases the
volume available for distribution of drugs.
 Disease States: Altered albumin or drug – binding protein conc.
 Altered or Reduced perfusion to organs /tissues
 Altered Tissue pH

WHAT ARE THE DETERMINANTS OF WHERE DRUGS GO?

Determinants of Drug Distribution:
• Organ blood flow
• Barriers to drug diffusion
• Adipose tissue
• Tissue protein binding
• Plasma protein binding
• Drug transport
• Ion trapping

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 WHAT IS THE EFFECT OF ORGAN BLOOD FLOW ON DRUG DISTRIBUTION?
• Organs with high blood flow will have larger amounts of drug delivered to them per unit
time.
• Organs with high blood flow will experience initial high concentrations of drug, but these
high concentrations will diminish as the drug is redistributed throughout the body to sites
with lower blood flow.
• Organs with high blood flow will experience larger initial effects.
• Many sedative/hypnotics, such as benzodiazepines
(e.g., diazepam,[Valium®]) will produce initial, but short-lived, profound CNS effects
following IV administration.

WHAT IS THE EFFECT OF BARRIERS TO DRUG DIFFUSION ON DRUG

DISTRIBUTION?
• Most capillaries have pores between the endothelial cells lining the capillaries.
• These pores allow for rapid diffusion of most drugs into the interstitial space.
• In some capillary beds, however, the endothelial cells are closely connected by “tight
junctions”, and such capillaries do not have pores between the endothelial cells.
WHAT IS THE EFFECT OF BARRIERS TO DRUG DIFFUSION ON DRUG
DISTRIBUTION?
• In capillaries with tight junctions, drug molecules must diffuse across (transcellular), rather
than around (paracellular) the endothelial cells.
• Only lipophilic drugs rapidly diffuse across capillary beds with tight junctions, whereas
hydrophilic drugs are mostly excluded.
WHAT IS THE EFFECT OF BARRIERS TO DRUG DIFFUSION ON DRUG
DISTRIBUTION?
The “blood-brain barrier (BBB)” is a special case:
• Capillaries in brain have tight junctions that contribute to the BBB.
• Capillaries in brain are wrapped by pericapillary glial cells that further contribute to the BBB.
• The endothelial cells in brain capillaries have P-glycoprotein that pumps drugs out of
endothelial cells, and this also contributes to the BBB.
• In general, the BBB restricts the movement of hydrophilic drugs into brain; however, the
BBB is “broken” by ischemia and inflammation.
• The BBB can be exploited to develop drugs with reduced CNS adverse effects.

WHAT IS THE EFFECT OF ADIPOSE TISSUE ON DRUG DISTRIBUTION?

• Lipophilic drugs will distribute into adipose (fat) tissue.
• Distribution of lipophilic drugs into fat may necessitate a larger initial bolus of drug to
achieve the desired effect.
• Large depots of drug in fat may necessitate a longer period of time for drug to be removed
from the body.
• The distribution of lipophilic drugs will be different in thin versus obese patients.

WHAT IS THE EFFECT OF TISSUE PROTEIN BINDING ON DRUG DISTRIBUTION?

• Some drugs are highly bound to tissue proteins.
• Binding of drugs by tissue may necessitate a larger initial bolus of drug to achieve the
desired effect.
• Large depots of drug in tissue may necessitate a longer period of time for drug to be removed
from the body.

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WHAT IS THE EFFECT OF PLASMA PROTEIN BINDING ON DRUG DISTRIBUTION?
• Some drugs are highly bound (> 90%) to plasma proteins.
• Acid drugs bind to albumin and basic drugs bind to alpha1-acid glycoprotein.
• Binding of drugs by plasma proteins limits the distribution of drugs out of the vascular
compartment, necessitating more drug initially to achieve the desired effect.
• Binding of drugs may limit the delivery of drugs to drug elimination mechanisms (for
example excretion by the kidney or metabolism by the liver), and this increases the time
required for the drug to be removed from the body.

WHAT IS THE EFFECT OF PLASMA PROTEIN BINDING ON DRUG DISTRIBUTION?

• Displacement of a highly plasma-protein bound drug by another drug may lead to drug-
drug interactions because of a rapid increase in the availability of “free” (unbound) drug.
• Displacement of unconjugated bilirubin from albumin by drugs may precipitate bilirubin
encephalopathy in newborns.

WHAT IS THE EFFECT OF DRUG TRANSPORT ON DRUG DISTRIBUTION?

• Transport mechanisms may increase or decrease the distribution of drugs to certain tissues.
For example, most diuretics are transported by the proximal tubules into the nephron, a
process that delivers the diuretics to their site of action.
• Competition for transport may result in drug-drug interactions.
For example, probenecid ( a drug used for gout) blocks the transport of diuretics into the
proximal tubule and thereby markedly blunts the effects of diuretics on salt and water
excretion.

WHAT IS THE EFFECT OF I0N TRAPPING ON DRUG DISTRIBUTION?

• Ion trapping can be used to distribute drugs into the urinary compartment to increase the
urinary excretion of poisons.
• Example: Alkalinization of the urine with systemic administration of sodium bicarbonate is
useful for the treatment of overdoses of aspirin and phenobarbital.
• Example: Acidification of the urine with systemic administration of ammonium chloride is
useful for the treatment of amphetamine overdoses.

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