Drug Distribution

Drug distribution

• Once a drug has gained access to the blood stream—

• It gets distributed to many organs including those not relevant to its

therapeutic effect
an analogy—

“If you sprinkle salt all over your plate, which has different eatable items, it is
not necessary that the salt will land only on one type of eatable.
Most of it may land on other parts of meal as well “
 Thus drug distribution means the pattern of “scattering” of specified
amount of drug among various locations within the body
 Fate of drug after absorption
• Bind/associate with receptor or site of action

• Get bound to plasma proteins

• Accumulate in various storage sites

• Enter into tissues which are not involved in its primary action

• Enter into tissue/organs where it is metabolized or excreted

Pathways of drug distribution
Drug may get distributed/ concentrated in various tissues—

I2 in thyroid

Fluoride in bones

Chloroquine in liver

Griseofulvin in keratin
 ????????
1. If we were to give a particular drug to act/distribute itself at a specific
site,,,,

—What are the hurdles/physiological barriers to achieve that ???

— What is the nature of the barrier ???

ALSO

If a drug crosses such a barrier, what are the consequences ???

 Physiological barriers to drug distribution
1. Blood brain barrier

2. Blood-CSF and CSF-brain barrier

3. Placental barrier
 Blood brain barrier (BBB)
• Many drugs used in therapeutics, may have wide distribution but do not
distribute/enter into brain

Because,,

• Endothelial cells of brain capillaries differ from peripheral capillaries.

Brain capillaries have—

1. Tight junctions (lack intercellular space or pores)

2. They have additional, enveloped less permeable glial cells

• This constitutes the morphology of blood brain barrier (BBB)

• They place constraints on the passage of drugs from blood to brain

Molecular barrier for distribution to Brain

• Other than morphological barrier, there are molecular barrier also

It include—

• Efflux pump/transporters : these transporters actively remove/efflux certain

drugs

e.g.,
p-glycoprotein (multidrug resistance protein 1- MDR1) coded by ABCC1 gene
Enzymatic barrier for distribution to Brain

• It include enzymes that are present in the capillary walls of brain —

• E.g. Monoamine oxidase (MAO), cholinesterase etc.

• They do not allow catecholamines (adrenaline etc), serotonin, acetylcholine,

etc. to enter brain in the active form
All these barrier (morphological, molecular and enzymatic) protects the brain
from –

1. Toxic substances

2. Neurotransmitters like adrenaline, noradrenaline, dopamine etc.

If these neurotransmitters or toxins were to access brain, it would have led to

serious adverse effects
 Drugs having access/distribution in brain

As a rule, only—

1. Lipid soluble drugs

2. Non-ionized form of drugs penetrate more easily to brain

E.g., of drugs distributed in brain

1. General anesthetic agents : Ether, halothane, thiopental and propofol

2. Narcotic analgesics: morphine, codeine

3. Anti-anxiety drugs : diazepam

Poor /no penetration is seen with—
1. Water soluble or Ionized form of drugs (polar compounds)

2. Quaternary substances (quaternary ammonium cations, are positively

charged polyatomic ions of the structure NR4+, R being an alkyl group or
an aryl group)
E.g. of drugs NOT distributed in brain

1. Polar compounds
• Neurotransmitters : dopamine, serotonin
• Antibiotics like gentamicin & streptomycin

2. Quaternary compounds
• d-tubocurarine (skeletal muscle relaxant)
• Acetylcholine (neurotransmitter)
• Neostigmine (used in myasthenia gravis)
NOTE: Inflammatory conditions such as—
✓Cerebral meningitis,
✓ Viral infections,
✓ Heat stress
All these can alter the permeability features of BBB

Drugs distributed in brain only in inflammatory conditions :

E.g.— Penicillins and chloramphenicol (antibiotic)

 Regions of brain deficient of Blood brain
barrier
• There are mainly 5 regions of brain which are relatively permeable or leaky

• There are no occluding zonulae at these sites

• So they DO NOT constitute BBB

1. Posterior pituitary gland

2. Pineal gland

3. median eminence

4. Choroid plexus capillaries

5. Area postrema (near fourth ventricle) including chemoreceptor trigger zone

(CTZ)
Regions lacking BBB
Significance of CTZ (chemoreceptor trigger zone) in emesis

• The vomiting center (VC) is located in the dorsolateral medulla. The VC

integrates input from cortex, limbic system, hypothalamus, vestibular centers,
gut etc. and induce vomiting reflex

• The CTZ (located within the dorsal surface of the medulla oblongata, in the floor of 4th
ventricle) is deficient of BBB

• CTZ contains receptors that detect emetic agents in the blood and relays
that information to the VC, which in turn, induces emesis
Because of this reason….

• Drugs which MAY NOT PRIMARILY enter brain due to BBB, can interact with CTZ
and induce vomiting.

• E.g. : several anti-cancer drugs (cisplatin etc)

 About choroid plexus capillaries
• CSF is secreted by the epithelial cells of the choroid plexus capillaries

• So one side (endothelial aspect) there is blood and other side (epithelial
aspect) there is CSF

• Epithelial/choroidal cells (of capillaries) are lined by occluding zonulae like

BBB

• This constitute blood-CSF barrier.

• So those drugs which DO NOT cross BBB, also, DO NOT cross Blood- CSF
barrier
Blood CSF barrier
Choroid plexus and CSF pathway (in blue)
 CSF- BRAIN barrier
Background
• Some of the drugs (given by oral or I.V) used in brain abscess/infections do
not gain entry into brain

• So they have to be administered directly by intrathecal route (into spinal

canal/CSF)

E.g,
• Amphotericin B (antifungal drug)
• Penicillin (anti bacterial drug)
• Once the drug is inside/dissolved in CSF, drug has to reach brain cells

• The wall of the ventricles (where CSF traverses) contain epithelial cells

• This layer constitutes CSF-brain barrier

• However this barrier is extremely permeable without any occluding zonulae

• So drugs given by intrathecal route attain sufficient concentration at brain to
treat CNS infections

Fate of this drug after action

• Exit of drugs from the CSF and brain is not dependent on lipid-solubility

• It is unrestricted.

• Bulk flow of CSF (along with the drug dissolved in it) occurs through the
arachnoid villi.
 Placental barrier
• The membrane of placenta is lipid in nature

• So readily allows transfer of lipid soluble and non-polar compounds by

passive diffusion

• Drugs distributed to fetus via placental barrier include—

Hypnotics (diazepam), opioids (morphine), digoxin (used in heart

failure) and many antibiotics etc
• There are other transport mechanisms also to allow passage of endogenous
substances—

1. Active transport (for amino acid and glucose)

2. Pinocytosis (for maternal immunoglobulin)

Drugs not allowed via placental barrier include—

1. Polar compounds – streptomycin and gentamicin (antibiotic)

2. Quaternary compounds— d-tubocurarine (skeletal muscle relaxant)

3. Substances with high molecular weight— dextran and insulin

 Importance of placental barrier
• When drugs are administered to pregnant women, some degree of fetal
exposure is likely to occur

• Consequences of such exposures are usually unknown

• So it is normally advised to severely restrict the usage of drugs at pregnancy

E.g of drugs which can cause adverse effects on fetus

1. In 1st trimister pregnancy – drugs can cause structural changes (congenital

abnormalities) to foetus

Such an effect by drug is called teratogenic effect

✓Thaliodmide (formerly used in morning sickness; now banned for this

indication— causes phocomelia)
Phocomelia by thalidomide
✓ Other : phenytoin (antiepileptic drug cause fetal hydantoin syndrome),
methotrexate (anti cancer drug causes microcephaly )

2. Drugs administered in last trimester may effect vital functions of fetus

✓Morphine causes fetal asphyxia

✓Anti-thyroid drugs can cause neonatal goitre
 Special compartments for drug distribution

• Most drugs get accumulated in those locations where they do not exert their
pharmacological actions

• However these can act as reservoirs for distribution eventually

E.g of drug reservoirs in distribution

1. Plasma protein binding as reservoir

2. Cellular reservoir
3. Transcellular reservoir
4. Fat as reservoir
5. Bones and connective tissue as reservoir
 Plasma protein binding as drug reservoir
• Drugs usually bind to plasma and cellular proteins in a –
✓Reversible manner and
✓Dynamic equilibrium

As in this equation

Free drug+ plasma Protein Drug-protein complex

• So extensive protein binding in blood serves as a circulating reservoir
Note:

• It is only free fraction of the drug is pharmacologically active for ACTION and
METABOLISM / EXCRETION

• Bound fraction is inert

• Because,,, it is only free fraction which can diffuse through capillary or blood
brain barrier (BBB) etc
• As the free and unbound drug is eliminated from the body—
more drug dissociates from the drug-plasma protein complex to
replace the free drug that was lost

• So, extensive protein binding does NOT prevent drug reaching its site of
action But, prolongs the drug availability and duration of action
 Important proteins that contribute to drug
binding
1. Plasma albumin

• Most important contributor to drug binding

• Most of the weak acidic drugs, in principle, bind to albumin—

✓Warfarin,
✓Penicillins etc.
2. α1 – acid glycoprotein (α1-AGP)
• Most lipophilic basic drugs bind to α1 – acid glycoprotein like—
✓Propranolol (antihypertensive),
✓lignocaine (local anaesthetic),
✓Chlorpromazine (antipsychotic)

Note:
• This glycoprotein is a acute phase reactant
meaning: plasma level increases in pathological states—
Myocardial infarction, arthritis, cancer, stress etc.
3. Tissue proteins and nucleoproteins
• Some drugs (having high apparent volume of distribution) specifically bind to
tissue proteins E.g. digoxin and chloroquine

4. miscellaneous binding proteins

Other proteins with e.g include—

✓Steroids bind to corticosteroid binding globulin or transcortin

✓Thyroxine bind to α globulins

✓Antigens bind to gamma globulins

 Clinical significance of plasma protein binding

1. Highly plasma protein bound drugs remain largely restricted to vascular

compartment . They tend to have lower volumes of distribution

2. Highly plasma protein bound drugs are difficult to be removed by

haemodialysis
3. The binding of drugs to plasma protein is a saturable process—
• Plasma level of albumin (synthesized by liver) reduces in pathological states
like –
✓Liver diseases
✓Uremia
✓All disease states causing hypoalbuminaemia

Implications:
✓Less plasma protein binding = ↑↑↑ free fraction of drug leading to toxic
effects (in some cases)
On the contrary,
• Disease states like myocardial infarction, stress, arthritis , Crohn’s disease
and other inflammatory diseases –
Increases the plasma levels of α1 – acid glycoprotein (α1-AGP)

Implications:

• Increased plasma protein binding = decreased free fraction of drug = low

therapeutic benefit
4. More than one drug can bind to same site of albumin

• This can give rise to displacement interactions between the drugs

• The drug bound with higher affinity will displace the one with lower affinity.

Some clinically important displacement interactions are:

❖Aspirin displaces sulfonylureas (anti-diabetic drug)

❖ Indomethacin (anti-inflammatory drug) and phenytoin (anti-epileptic drug)

displaces warfarin (anticoagulant)
Note:
Acidic drugs (bound to albumin) DO NOT displace the basic drugs (bound to
α1— acid glycoprotein) and vice versa

• Theoretically, Displaced drugs (leading to increased free drug

concentration) should result in potential adverse effects

• However, practically, increased level of free drug is only transient and are
quickly metabolized or gets diffused into tissues
 apparent Volume of distribution (aVd or VD or
V)
Background:

• When 500 mcg of digoxin (used in heart failure) is administered,

it provides a plasma concentration of 0.78 mcg/L in a 70 Kg adult
person.
From this it means,,,

• If 0.78 mcg of digoxin is contained in 1 L of plasma, 500 mcg of digoxin would

require_????_________________

0.78 mcg 1 L of plasma

500 mcg ?????

Ans : 641 L of plasma to reach same concentration

Neither there is so much plasma nor even so much body volume.

Intracellular : 28 L
Interstitial volume : 10 L
Plasma volume : 4 L
Total : 42 L

• Therefore, Digoxin, exhibits volume of distribution far in excess (16 times

higher) of total body water
• This is impossible to explain and serve to emphasize that-

1. Volume of distribution does NOT represent REAL Volume

• “It must be regarded as the size of the pool of the body or fluids that would
be theoretically required if the drug was distributed equally throughout all
portions of the body “

2. This drug is widely distributed in the body including muscles and adipose
tissue, leaving a small fraction to be distributed in plasma
So apparent Volume of Distribution (aVd) means—

“The theoretical space/volume that should be apparently necessary to

contain the total amount of an administered drug at the same concentration
that it is observed in the plasma”
OR
“the volume that would accommodate all the drug in the body, if the
concentration throughout was the same as in plasma”.
aVd is expressed in L or L/70 kg and L/kg
 Implications and generalizations from aVd or
VD
1. If the drug does NOT cross capillary walls (because high molecular weight) like
Heparin
Insulin
and is given by I.V—

its aVd is equal to plasma water i.e., 4 L or 4L /70 kg or 0.05 L/kg

2. Drugs highly bound to plasma protein (less bound to tissue protein) have a
low aVd value

e.g. warfarin (anticoagulant) 8L, furosemide 9L (diuretic)

3. Conversely, lesser the plasma protein binding and higher is the tissue binding
= greater is aVd for the drug
E.g
Chloroquine (aVd is around 250-302 L/kg or 15,000 L in a 70 kg adult)
4. aVd of many drugs may be much more than actual body volume (digoxin,
morphine etc)

• Because, they are even bound to muscles and adipose tissue

• Such drugs are difficult to be removed by haemodialysis if toxicity appears

• Dialysis is helpful only for those drugs having smaller aVd (warfarin : 8 L, aspirin
: 11.9 L etc)
Generally,
• A value of aVd <5L implies :
that the drug is retained within the vascular compartment (heparin,
insulin)

• A value of approximating 15 L suggests

that the drug is restricted to extracellular compartment (aspirin,
gentamicin)
• Large volume of distribution > 20 L indicates
✓distribution throughout the body water (ethanol, phenytoin )

or

✓Penetration in various tissues (digoxin, chloroquine)

 Redistribution of drugs

• 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

• So 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

• Anaesthetic action of thiopentone sod. Injected i.v. is terminated in few
minutes due to redistribution.

• Elimination t ½ of sedative hypnotics like diazepam and nitrazepam is > 30

hr.
However due to redistribution, hypnotic action lasts for only 6–8
hours.
 FAQs

• Describe the clinical significance of drug plasma protein binding (5 mark)

• Define apparent volume of distribution and mention its clinical significance

(5 mark)
Dr Advaitha M V
Asst Professor
Dept of Pharmacology